Nitrogen-containing heterocyclic compounds as fxr modulators

ABSTRACT

The present technology is directed to compounds, compositions, and methods related to modulation of FXR. In particular, the present compounds and compositions may be used to treat FXR-mediated disorders and conditions, including, e.g., liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, and atherosclerosis, and renal disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/346807, filed on May 1, 2019, which is a U.S. National StageApplication under 35 U.S.C. § 371 of International Application No.PCT/US2017/058802, filed on Oct. 27, 2017, which claims the benefit ofclaims priority to U.S. Provisional Application No. 62/424813, filed onNov. 21, 2016, and Chinese Application No. 201610974016.1, filed on Nov.4, 2016, each of which is incorporated by reference in their entirity.

FIELD

The present technology is directed to compounds, compositions, andmethods related to modulation of farnesoid X receptor (FXR). Inparticular, the present compounds and compositions may be used to treatFXR-mediated disorders and conditions, including, e.g., liver disease,hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome,cardiovascular disease, gastrointestinal disease, atherosclerosis, andrenal disease.

BACKGROUND

The Farnesoid X receptor (FXR, NR1H4) is an orphan member of the nuclearreceptor gene family that is activated by farnesol metabolites (Formanet al. “Identification of a nuclear receptor that is activated byfarnesol metabolites” Cell 1995, 81, 687-693; Seol et al. “Isolation ofproteins that interact specifically with the retinoid X receptor: twonovel orphan receptors” Mol. Endocrinol. 1995, 9, 72-85). FXR is highlyexpressed in the liver, gall bladder, intestine, kidney and adrenalglands.

Subsequently, bile acids were identified as natural ligands for FXR.Bile acid has many physiological functions and plays a critical role inthe digestion, absorption, transportation, distribution of fat andlipid-soluble vitamins; maintain homeostasis of cholesterol and glucose.Through regulation of gene expression of bile acids, FXR serves as a keycontroller of bile acid homeostasis. Therefore, FXR modulation isexpected to provide treatments for diseases such as cholestasis, liverfibrosis, liver cancer, atherosclerosis, diabetes and the like. FXRagonists were also reported as a treatment option for HBV infection(Radreau et al. “Reciprocal regulation of farnesoid X receptor aactivity and hepatitis B virus replication in differentiated HepaRGcells and primary human hepatocytes” FASEB J, 2016, 30, 3146-3154).

In recent years, a variety of primary and secondary bile acids such aschenodeoxycholic acid (CDCA) that can activate FXR have been found. In2002, Pellicciari et al. reported the first synthesis of highly activesteroid FXR agonist, 6-ethyl-CDCA (Pellicciari et al.“6a-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXRagonist endowed with anticholestatic activity” J. Med. Chem. 2002, 45,3569-72). 6-EDCA, also known as obeticholic acid, is in clinical trialsfor treatment of NAFLD, NASH, liver cirrhosis and other liverconditions. It has been approved for treatment in the US for thetreatment of primary biliary cholangitis. Thus, FXR modulators have beenshown to be therapeutically effective in a number of FXR-mediateddiseases and disorders.

SUMMARY

In one aspect, the present technology provides a compound according toformula I

stereoisomers, and/or salts thereof; wherein

-   L and M are independently selected from N and CR⁷, provided that at    least one of L and M is N;-   Z is a substituted or unsubstituted C₁-C₄ alkylene, O—C₁-C₄    alkylene, cyclopropylalkylene, or oxetanylalkylene group;-   W is

-   X is

-   D is N or CR⁹;-   one of G¹, G², G³, and G⁴ is CR¹³ and the others are selected from    the group consisting of CH and CR¹¹;-   Q is O, S, or NR¹²;-   R¹ and R² are independently H, OH, halo, CN, carboxyl, NR^(a)R^(b),    or a substituted or unsubstituted alkyl, alkoxy, or hydroxyalkyl    group;-   R³ is a substituted or unsubstituted alkyl or cycloalkyl group;-   R⁴ is CN, SO₃H, CONR^(a)R^(b), SO₂NR^(a)R^(b), NHSO₂R^(b),    SO₂NHCOR^(a), CO₂R^(c), or a substituted or unsubstituted tetrazolyl    or 1,2,4-oxadiazol-5(4H)-one-3-yl group;-   R⁷ is H, OH, halo, CN, carboxyl, amido, NR^(a)R^(b), or a    substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, or    aminoalkyl group;-   R⁹ and R¹³ are independently H, halo, or a substituted or    unsubstituted C₁-C₆ alkyl, or O—(C₁-C₆ alkyl) group;-   R¹⁰ at each occurrence is independently halo, CO₂R^(c), or a    substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl,    cycloalkyl, or fluorinated cycloalkyl group, or, when n is 2 or 3,    two of the R¹⁰ groups together may be a substituted or unsubstituted    C2-C5 alkylene, heteroalkylene, alkenylene or heteroalkenylene group    having 2 separate points of attachment to the same carbon or    different carbons of the nitrogen containing ring to which it is    attached;-   R¹¹ at each occurrence are independently OH, halo, CF₃, CN,    carboxyl, NR^(a)R^(b), or a substituted or unsubstituted alkyl,    alkoxy group, or phenyl group;-   R¹² is H or a substituted or unsubstituted C₁-C₆ alkyl group; and-   R^(a) at each occurrence is independently H, or a substituted or    unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, or SO₂-alkyl    group;-   R^(b) at each occurrence is H or a substituted or unsubstituted    alkyl, or haloalkyl group;-   R^(c) is H or a substituted or unsubstituted alkyl, alkenyl,    alkynyl, or cycloalkyl group;-   n is 0, 1, 2, 3, or 4; and-   r and t are each independently 1, 2, or 3.

In a second aspect, the present technology provides a compound accordingto formula IA, IB, or IC:

-   stereoisomers, and/or salts thereof; wherein-   A¹, A², A³, and A⁴ are independently selected from the group    consisting of CR⁵R⁶ and NR⁸, or when involved in a double bond, are    selected from the group consisting of CR⁵ and N, provided that not    more than two of A¹, A², A³, and A⁴ are N or NR⁸;-   L and M are independently N or CR⁷;-   Z is a substituted or unsubstituted C₁-C₄ alkylene, O—C¹-C⁴    alkylene, cyclopropylalkylene, or oxetanylalkylene group;-   W is

-   X is

-   D is N or CR⁹;-   D¹, D² and D³ are independently selected from CH or CR¹⁴, and    optionally one of D¹, D² and D³ is N;-   one of G¹, G², G³, and G⁴ is CR¹³ and the others are selected from    the group consisting of CH, CR¹¹, and N, provided that not more than    one of G¹, G², G³, and G⁴ is N;-   Q is O, S, or NR¹²;-   R¹ and R² are independently H, OH, halo, CN, carboxyl, NR^(a)R^(b),    or a substituted or unsubstituted alkyl, alkoxy, or hydroxyalkyl    group;-   R³ is a substituted or unsubstituted alkyl or cycloalkyl group;-   R⁴ is CN, SO₃H, CONR^(a)R^(b), SO₂NR^(a)R^(b), NHSO₂R^(b),    SO₂NHCOR^(a), CO₂R^(c), or a substituted or unsubstituted tetrazolyl    or 1,2,4-oxadiazol-5(4H)-one-3-yl group;-   R⁵ and R⁷ are independently H, OH, halo, CN, carboxyl, amido,    NR^(a)R^(b), or a substituted or unsubstituted alkyl, alkoxy,    hydroxyalkyl, or aminoalkyl group;-   R⁶ at each occurrence is independently H, OH, halo, CN, carboxyl,    amido, NR^(a)R^(b), or a substituted or unsubstituted alkyl, alkoxy,    hydroxyalkyl, or aminoalkyl group;-   R⁸ at each occurrence is independently H or a substituted or    unsubstituted alkyl group;-   R⁹ and R¹³ are independently H, halo, or a substituted or    unsubstituted C₁-C₆ alkyl, or O—(C₁-C₆ alkyl) group;-   R¹⁰ at each occurrence is independently halo, CO₂R^(c), or a    substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl,    cycloalkyl, or fluorinated cycloalkyl group;-   R¹¹ and R¹⁴ at each occurrence are independently OH, halo, CF₃, CN,    carboxyl, NR^(a)R^(b), or a substituted or unsubstituted alkyl,    alkoxy group, or phenyl group;-   R¹² is H or a substituted or unsubstituted C₁-C₆ alkyl group; and-   R^(a) at each occurrence is independently H, or a substituted or    unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, or SO₂-alkyl    group;-   R^(b) at each occurrence is H or a substituted or unsubstituted    alkyl, or haloalkyl group;-   R^(c) is H or a substituted or unsubstituted alkyl, alkenyl,    alkynyl, or cycloalkyl group;-   n is 0, 1, 2, 3, or 4;-   r and t are each independently 1, 2, or 3; and-   indicates a single or double bond.

In a related aspect, a composition is provided that includes thecompound of any one of the compounds disclosed herein (including but notlimited to compounds of formulae I, IA, IB, and IC) and apharmaceutically accepT carrier.

In another aspect, a pharmaceutical composition is provided, thepharmaceutical composition including an effective amount of the compoundof any one of the above embodiments for treating an FXR-mediateddisorder or condition.

In another aspect, a method is provided that includes administering aneffective amount of a compound of any one of the above embodiments, oradministering a pharmaceutical composition including an effective amountof a compound of any one of the above embodiments, to a subjectsuffering from an FXR-mediated disorder or condition.

In another aspect, a method is provided that includes modulating FXR ina subject by contacting FXR with an effective amount of a compound ofany one of the compounds of described herein, including but not limitedto compounds of formulae I, IA, IB, and IC.

DETAILED DESCRIPTION

In various aspects, the present technology provides compounds andmethods for modulating FXR and the treatment of FXR-mediated disordersand conditions. The compounds provided herein can be formulated intopharmaceutical compositions and medicaments that are useful in thedisclosed methods. Also provided is the use of the compounds inpreparing pharmaceutical formulations and medicaments.

The following terms are used throughout as defined below.

As used herein and in the appended claims, singular articles such as “a”and “an” and “the” and similar referents in the context of describingthe elements (especially in the context of the following claims) are tobe construed to cover both the singular and the plural, unless otherwiseindicated herein or clearly contradicted by context. Recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterilluminate the embodiments and does not pose a limitation on the scopeof the claims unless otherwise stated. No language in the specificationshould be construed as indicating any non-claimed element as essential.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particular term.

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it also includes deuterium andtritium. Compounds comprising radioisotopes such as tritium, C¹⁴, P³²and S³⁵ are thus within the scope of the present technology. Proceduresfor inserting such labels into the compounds of the present technologywill be readily apparent to those skilled in the art based on thedisclosure herein.

In general, “substituted” refers to an organic group as defined below(e.g., an alkyl group) in which one or more bonds to a hydrogen atomcontained therein are replaced by a bond to non-hydrogen or non-carbonatoms. Substituted groups also include groups in which one or more bondsto a carbon(s) or hydrogen(s) atom are replaced by one or more bonds,including double or triple bonds, to a heteroatom. Thus, a substitutedgroup is substituted with one or more substituents, unless otherwisespecified. In some embodiments, a substituted group is substituted with1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groupsinclude: halogens (i.e., F, Cl, Br, and I); CF₃; hydroxyls; alkoxy,alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo);carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines;aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls;pentafluorosulfanyl (i.e., SF₅), sulfonamides; amines; N-oxides;hydrazines; hydrazides; hydrazones; azides; amides; amines; ureas;amidines; guanidines; enamines; imides; isocyanates; isothiocyanates;cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); andthe like.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and ring systemsin which a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted cycloalkyl, aryl, heterocyclyl andheteroaryl groups may also be substituted with substituted orunsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

Alkyl groups include straight chain and branched chain alkyl groupshaving from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or,in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms.Examples of straight chain alkyl groups include groups such as methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octylgroups. Examples of branched alkyl groups include, but are not limitedto, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl,and 2,2-dimethylpropyl groups. Representative substituted alkyl groupsmay be substituted one or more times with substituents such as thoselisted above, and include without limitation haloalkyl (e.g.,trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups havingfrom 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocycliccycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In someembodiments, the cycloalkyl group has 3 to 8 ring members, whereas inother embodiments the number of ring carbon atoms range from 3 to 5, 3to 6, or 3 to 7. Bi- and tricyclic ring systems include both bridgedcycloalkyl groups and fused rings, such as, but not limited to,bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like. Substitutedcycloalkyl groups may be substituted one or more times with,non-hydrogen and non-carbon groups as defined above. However,substituted cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups may be mono-substituted orsubstituted more than once, such as, but not limited to, 2,2-, 2,3-,2,4-, 2,5- or 2,6-disubstituted cyclohexyl groups, which may besubstituted with substituents such as those listed above.

Cycloalkylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to acycloalkyl group as defined above. In some embodiments, cycloalkylalkylgroups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, andtypically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups maybe substituted at the alkyl, the cycloalkyl or both the alkyl andcycloalkyl portions of the group. Representative substitutedcycloalkylalkyl groups may be mono-substituted or substituted more thanonce, such as, but not limited to, mono-, di- or tri-substituted withsubstituents such as those listed above.

Alkenyl groups include straight and branched chain alkyl groups asdefined above, except that at least one double bond exists between twocarbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, andtypically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group hasone, two, or three carbon-carbon double bonds. Examples include, but arenot limited to vinyl, allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, among others. Representativesubstituted alkenyl groups may be mono-substituted or substituted morethan once, such as, but not limited to, mono-, di- or tri-substitutedwith substituents such as those listed above.

Cycloalkenyl groups include cycloalkyl groups as defined above, havingat least one double bond between two carbon atoms. In some embodimentsthe cycloalkenyl group may have one, two or three double bonds but doesnot include aromatic compounds. Cycloalkenyl groups have from 4 to 14carbon atoms, or, in some embodiments, 5 to 14 carbon atoms, 5 to 10carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples ofcycloalkenyl groups include cyclohexenyl, cyclopentenyl,cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

Cycloalkenylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above. Substituted cycloalkenylalkylgroups may be substituted at the alkyl, the cycloalkenyl or both thealkyl and cycloalkenyl portions of the group. Representative substitutedcycloalkenylalkyl groups may be substituted one or more times withsubstituents such as those listed above.

Alkynyl groups include straight and branched chain alkyl groups asdefined above, except that at least one triple bond exists between twocarbon atoms. Alkynyl groups have from 2 to 12 carbon atoms, andtypically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group hasone, two, or three carbon-carbon triple bonds. Examples include, but arenot limited to —C≡CH, —C≡CCH₃, —CH₂C≡CCH₃, —C≡CCH₂CH(CH₂CH₃)₂, amongothers. Representative substituted alkynyl groups may bemono-substituted or substituted more than once, such as, but not limitedto, mono-, di- or tri-substituted with substituents such as those listedabove.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Aryl groups herein include monocyclic, bicyclic andtricyclic ring systems. Thus, aryl groups include, but are not limitedto, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl,anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In someembodiments, aryl groups contain 6-14 carbons, and in others from 6 to12 or even 6-10 carbon atoms in the ring portions of the groups. In someembodiments, the aryl groups are phenyl or naphthyl. Although the phrase“aryl groups” includes groups containing fused rings, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like), it does not include aryl groups that have other groups, suchas alkyl or halo groups, bonded to one of the ring members. Rather,groups such as tolyl are referred to as substituted aryl groups.Representative substituted aryl groups may be mono-substituted orsubstituted more than once. For example, monosubstituted aryl groupsinclude, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenylor naphthyl groups, which may be substituted with substituents such asthose listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. In some embodiments, aralkyl groups contain 7 to 16carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substitutedaralkyl groups may be substituted at the alkyl, the aryl or both thealkyl and aryl portions of the group. Representative aralkyl groupsinclude but are not limited to benzyl and phenethyl groups and fused(cycloalkylaryl)alkyl groups such as 4-indanylethyl. Representativesubstituted aralkyl groups may be substituted one or more times withsubstituents such as those listed above.

Heteroalkyl groups are alkyl groups in which 1 or 2 carbons are replacedwith a heteroatom selected from N, O or S. Thus, heteroalkyl groups mayinclude straight chain and branched chain heteroalkyl groups having from1 to 11 carbon atoms, and typically from 1 to 10 carbons or, in someembodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Heteroalkylgroups include for example, methoxy, methoxyethyl, methylthio,methylthiopropyl, ethyloxymethyl, and methylaminobutyl. Heteroalkylgroups may be substituted one or more times just as alkyl groups arewith substituents such as those listed above.

Heterocyclyl groups include aromatic (also referred to as heteroaryl)and non-aromatic ring compounds containing 3 or more ring members, ofwhich one or more is a heteroatom such as, but not limited to, N, O, andS. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4heteroatoms. In some embodiments, heterocyclyl groups include mono-, bi-and tricyclic rings having 3 to 16 ring members, whereas other suchgroups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members.Heterocyclyl groups encompass aromatic, partially unsaturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase “heterocyclyl group” includesfused ring species including those comprising fused aromatic andnon-aromatic groups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. However, the phrase does notinclude heterocyclyl groups that have other groups, such as alkyl, oxoor halo groups, bonded to one of the ring members. Rather, these arereferred to as “substituted heterocyclyl groups”. Heterocyclyl groupsinclude, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl,tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl,imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolonyl (including 1,2,4-oxazol-5(4H)-one-3-yl),isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl,pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl,quinuclidyl, indolyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl),indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl,benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl,benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl,imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl(pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl(azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl,adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fusedring compounds in which all rings are aromatic such as indolyl groupsand include fused ring compounds in which only one of the rings isaromatic, such as 2,3-dihydro indolyl groups. Although the phrase“heteroaryl groups” includes fused ring compounds, the phrase does notinclude heteroaryl groups that have other groups bonded to one of thering members, such as alkyl groups. Rather, heteroaryl groups with suchsubstitution are referred to as “substituted heteroaryl groups.”Representative substituted heteroaryl groups may be substituted one ormore times with various substituents such as those listed above.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above. Substituted heterocyclylalkylgroups may be substituted at the alkyl, the heterocyclyl or both thealkyl and heterocyclyl portions of the group. Representativeheterocyclyl alkyl groups include, but are not limited to,morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl,pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl.Representative substituted heterocyclylalkyl groups may be substitutedone or more times with substituents such as those listed above.

Heteroaralkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above. Substituted heteroaralkyl groups maybe substituted at the alkyl, the heteroaryl or both the alkyl andheteroaryl portions of the group. Representative substitutedheteroaralkyl groups may be substituted one or more times withsubstituents such as those listed above.

Groups described herein having two or more points of attachment (i.e.,divalent, trivalent, or polyvalent) within the compound of the presenttechnology are designated by use of the suffix, “ene.” For example,divalent alkyl groups are alkylene groups; divalent aryl groups arearylene groups; divalent heteroalkyl groups are heteroalkylene groups;heteroaryl groups are divalent heteroarylene groups; and so forth.Substituted groups having a single point of attachment to the compoundof the present technology are not referred to using the “ene”designation. Thus, e.g., chloroethyl is not referred to herein aschloroethylene.

Alkoxy groups are hydroxyl groups (—OH) in which the bond to thehydrogen atom is replaced by a bond to a carbon atom of a substituted orunsubstituted alkyl group as defined above. Examples of linear alkoxygroups include but are not limited to methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy, and the like. Examples of branched alkoxy groupsinclude but are not limited to isopropoxy, sec-butoxy, tert-butoxy,isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groupsinclude but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like. Representative substitutedalkoxy groups may be substituted one or more times with substituentssuch as those listed above.

The terms “alkanoyl” and “alkanoyloxy” as used herein can refer,respectively, to —C(O)-alkyl groups and —O—C(O)-alkyl groups, eachcontaining 2-5 carbon atoms. Similarly, “aryloyl” and “aryloyloxy” referto —C(O)-aryl groups and —O—C(O)-aryl groups.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, asubstituted or unsubstituted aryl group bonded to an oxygen atom and asubstituted or unsubstituted aralkyl group bonded to the oxygen atom atthe alkyl. Examples include but are not limited to phenoxy, naphthyloxy,and benzyloxy. Representative substituted aryloxy and arylalkoxy groupsmay be substituted one or more times with substituents such as thoselisted above.

The term “carboxylate” as used herein refers to a —COOH group.

The term “ester” as used herein refers to —COOR⁷⁰ and —C(O)O-G groups.R⁷⁰ is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl,alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group asdefined herein. G is a carboxylate protecting group. Carboxylateprotecting groups are well known to one of ordinary skill in the art. Anextensive list of protecting groups for the carboxylate groupfunctionality may be found in Protective Groups in Organic Synthesis,Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rdEdition, 1999) which can be added or removed using the procedures setforth therein and which is hereby incorporated by reference in itsentirety and for any and all purposes as if fully set forth herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR⁷¹R⁷², and —NR⁷¹C(O)R⁷² groups, respectively. R⁷¹ and R⁷² areindependently hydrogen, or a substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl orheterocyclyl group as defined herein. Amido groups therefore include butare not limited to carbamoyl groups (—C(O)NH₂) and formamide groups(—NHC(O)H). In some embodiments, the amide is —NR⁷¹C(O)—(C₁₋₅ alkyl) andthe group is termed “carbonylamino,” and in others the amide is—NHC(O)-alkyl and the group is termed “alkanoylamino.”

The term “nitrile” or “cyano” as used herein refers to the —CN group.

Urethane groups include N- and O-urethane groups, i.e., —NR⁷³C(O)OR⁷⁴and —OC(O)NR⁷³R⁷⁴ groups, respectively. R⁷³ and R⁷⁴ are independently asubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R⁷³may also be H.

The term “amine” (or “amino”) as used herein refers to —NR⁷⁵R⁷⁶ groups,wherein R⁷⁵ and R⁷⁶ are independently hydrogen, or a substituted orunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclylalkyl or heterocyclyl group as defined herein. In someembodiments, the amine is alkylamino, dialkylamino, arylamino, oralkylarylamino. In other embodiments, the amine is NH₂, methylamino,dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino,phenylamino, or benzylamino.

The term “sulfonamido” includes S- and N-sulfonamide groups, i.e.,—SO₂NR⁷⁸R⁷⁹ and —NR⁷⁸SO₂R⁷⁹ groups, respectively. R⁷⁸ and R⁷⁹ areindependently hydrogen, or a substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, orheterocyclyl group as defined herein. Sulfonamido groups thereforeinclude but are not limited to sulfamoyl groups (—SO₂NH₂). In someembodiments herein, the sulfonamido is —NHSO₂-alkyl and is referred toas the “alkylsulfonylamino” group.

The term “thiol” refers to —SH groups, while “sulfides” include —SR⁸⁰groups, “sulfoxides” include —S(O)R⁸¹ groups, “sulfones” include —SO₂R⁸²groups, and “sulfonyls” include —SO₂OR⁸³. R⁸⁰, R⁸¹, R⁸², and R⁸³ areeach independently a substituted or unsubstituted alkyl, cycloalkyl,alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl groupas defined herein. In some embodiments the sulfide is an alkylthiogroup, —S-alkyl.

The term “urea” refers to —NR⁸⁴—C(O)—NR⁸⁵R⁸⁶ groups. R⁸⁴, R⁸⁵, and R⁸⁶groups are independently hydrogen, or a substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, orheterocyclylalkyl group as defined herein.

The term “amidine” refers to —C(NR⁸⁷)NR⁸⁸R⁸⁹ and —NR⁸⁷C(NR⁸⁸)R⁸⁹,wherein R⁸⁷, R⁸⁸, and R⁸⁹ are each independently hydrogen, or asubstituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

The term “guanidine” refers to —NR⁹⁰C(NR⁹¹)NR⁹²R⁹³, wherein R⁹⁰, R⁹¹,R⁹² and R⁹³ are each independently hydrogen, or a substituted orunsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl,heterocyclyl or heterocyclylalkyl group as defined herein.

The term “enamine” refers to —C(R⁹⁴)═C(R⁹⁵)NR⁹⁶R⁹⁷ and—NR⁹⁴C(R⁹⁵)═C(R⁹⁶)R⁹⁷, wherein R⁹⁴, R⁹⁵, R⁹⁶ and R⁹⁷ are eachindependently hydrogen, a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

The term “halogen” or “halo” as used herein refers to bromine, chlorine,fluorine, or iodine. In some embodiments, the halogen is fluorine. Inother embodiments, the halogen is chlorine or bromine.

The term “hydroxyl” as used herein can refer to —OH or its ionized form,—O—. A “hydroxyalkyl” group is a hydroxyl-substituted alkyl group, suchas HO—CH₂—.

The term “imide” refers to —C(O)NR⁹⁸C(O)R⁹⁹, wherein R⁹⁸ and R⁹⁹ areeach independently hydrogen, or a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

The term “imine” refers to —CR¹⁰⁰(NR¹⁰⁰) and —N(CR¹⁰⁰R¹⁰¹) groups,wherein R¹⁰⁰ and R¹⁰¹ are each independently hydrogen or a substitutedor unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl,heterocyclyl or heterocyclylalkyl group as defined herein, with theproviso that R¹⁰⁰ and R¹⁰¹ are not both simultaneously hydrogen.

The term “nitro” as used herein refers to an —NO₂ group.

The term “trifluoromethyl” as used herein refers to —CF₃.

The term “trifluoromethoxy” as used herein refers to —OCF₃.

The term “azido” refers to —N₃.

The term “trialkyl ammonium” refers to a —N(alkyl)₃ group. Atrialkylammonium group is positively charged and thus typically has anassociated anion, such as halogen anion.

The term “isocyano” refers to —NC.

The term “isothiocyano” refers to —NCS.

The phrase “selectively modulates” as used herein will be understood bypersons of ordinary skill in the art and will vary to some extentdepending upon the context in which the phrase is used. If there areuses of the phrase which are not clear to persons of ordinary skill inthe art, given the context in which the phrase is used, the phrase atminimum refers to the compounds acting through a specific mechanism ofaction, resulting in fewer off-target effects because the compoundstarget a particular receptor over other receptors, such as an FXR over aGR receptor, LXR, PPARγ, TGR5 or PXR. This phrase may further bemodified as discussed herein.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember. Thus, for example, a group having 1-3 atoms refers to groupshaving 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers togroups having 1, 2, 3, 4, or 5 atoms, and so forth.

Pharmaceutically acceptable salts of compounds described herein arewithin the scope of the present technology and include acid or baseaddition salts which retain the desired pharmacological activity and isnot biologically undesirable (e.g., the salt is not unduly toxic,allergenic, or irritating, and is bioavailable). When the compound ofthe present technology has a basic group, such as, for example, an aminogroup, pharmaceutically acceptable salts can be formed with inorganicacids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuricacid, and phosphoric acid), organic acids (e.g. alginate, formic acid,acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid,tartaric acid, lactic acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (suchas aspartic acid and glutamic acid). When the compound of the presenttechnology has an acidic group, such as for example, a carboxylic acidgroup, it can form salts with metals, such as alkali and earth alkalimetals (e.g. Na⁺, Li⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺), ammonia or organic amines(e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine) or basic aminoacids (e.g. arginine, lysine and ornithine). Such salts can be preparedin situ during isolation and purification of the compounds or byseparately reacting the purified compound in its free base or free acidform with a suitable acid or base, respectively, and isolating the saltthus formed.

Those of skill in the art will appreciate that compounds of the presenttechnology may exhibit the phenomena of tautomerism, conformationalisomerism, geometric isomerism and/or stereoisomerism. As the formuladrawings within the specification and claims can represent only one ofthe possible tautomeric, conformational isomeric, stereochemical orgeometric isomeric forms, it should be understood that the presenttechnology encompasses any tautomeric, conformational isomeric,stereochemical and/or geometric isomeric forms of the compounds havingone or more of the utilities described herein, as well as mixtures ofthese various different forms.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The presence and concentrations of theisomeric forms will depend on the environment the compound is found inand may be different depending upon, for example, whether the compoundis a solid or is in an organic or aqueous solution. For example, inaqueous solution, guanidines may exhibit the following isomeric forms inprotic organic solution, also referred to as tautomers of each other:

Because of the limits of representing compounds by structural formulas,it is to be understood that all chemical formulas of the compoundsdescribed herein represent all tautomeric forms of compounds and arewithin the scope of the present technology.

Stereoisomers of compounds (also known as optical isomers) include allchiral, diastereomeric, and racemic forms of a structure, unless thespecific stereochemistry is expressly indicated. Thus, compounds used inthe present technology include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions. Bothracemic and diastereomeric mixtures, as well as the individual opticalisomers can be isolated or synthesized so as to be substantially free oftheir enantiomeric or diastereomeric partners, and these stereoisomersare all within the scope of the present technology.

In one aspect, the present technology provides heterocyclic derivativessuch as pyrrolidines, imidazolidines, piperidines, piperazines, azepanesand diazepanes that modulate FXR and intermediates for making suchcompounds. The compounds include, but are not limited to compounds offormulae I, IA, IB, and IC as described herein.

In some aspects or embodiments of compounds of the present technology,compounds of formula IA are provided:

wherein X, L, Z, W, R⁴, R¹⁰, n, r, and t may have any of the values ofany of the aspects or embodiments of compounds described herein. Incertain such embodiments, L is N. In other embodiments, L is CR⁷.

In some aspects or embodiments of compounds of the present technology,compounds of formula IB are provided:

wherein X, M, Z, W, R⁴, R¹⁰, n, r, and t may have any of the values ofany of the aspects or embodiments of compounds described herein. Incertain embodiments of compounds of formula IB, M is N. In otherembodiments, M is CR⁷.

In some aspects and embodiments of the present compounds (including butnot limited to compounds of formulae I, IA, IB, and IC), r and t areeach independently 1, 2, or 3, as noted above. In certain embodiments, ris 1 or 2. In some embodiments, r is 2. In some embodiments, t is 1. Inother embodiments t is 2. In some embodiments t is 3. In someembodiments, the sum of r+t is greater than 2 but less than 6 (i.e.,2<r+t<6). Thus, in some embodiments the present compounds include butare not limited to pyrrolidines, piperidines, piperazines, azepanes anddiazepanes. For example, in some embodiments compounds of formula Iinclude, but are not limited to, compounds of formulas IA1 (r=1, t=2,L=CH), IA2 (r=2, t=2, L=CH), IA3 (r=2, t=2, L=N), IA4 (r=2, t=3, L=CH),and IA5 (r=2, t=3, L=N), below. In other embodiments, compounds offormula I include but are not limited to compounds of formulas IB1 (r=1,t=2, M=CH), IB2 (r=1, t=2, M=N), IB3 (r=2, t=2, M=CH), and IB4 (r=2,t=3, M=CH), below.

In some embodiments, n is 1 or 2. In some embodiments, n is 0. In someembodiments, R¹⁰ at each occurrence is independently halo, CO₂R^(c), ora substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl,or fluorinated cycloalkyl group. For example, in some embodiments, R¹⁰at each occurrence is independently CO₂H, substituted or unsubstitutedC₁-C₃ alkyl, C₁-C₃ hydroxyalkyl, or C₃-C₆ cycloalkyl group. In someembodiments, R¹⁰ at each occurrence is independently CO₂H, CH₃, CH₂OH,or a cyclopropyl group. In other embodiments, R¹⁰ at each occurrence isindependently CH₃, CH₂CH₃, or CH(CH₃)₂. In certain embodiments, when nis 2 or 3, two of the R¹⁰ groups together may be a substituted orunsubstituted C2-C5 (i.e., a C2, C3, C4, or C5 alkylene group) alkylene,heteroalkylene, alkenylene or heteroalkenylene group having 2 separatepoints of attachment to the same carbon or different carbons of thenitrogen containing ring to which it is attached. In some suchembodiments, R¹⁰ may be a substituted or unsubstituted C2-C5 alkylenegroup having 2 separate points of attachment to the same carbon ordifferent carbons of the nitrogen containing ring to which it isattached. In some such embodiments, R¹⁰ is an unsubstituted C2-C5alkylene group having 2 separate points of attachment to the samecarbon, thus forming a spirocyclic group (e.g., a spirocycliccyclopropyl group, spirocyclic cyclobutyl group, spirocyclic cyclopentylgroup, spirocyclic cyclohexyl group). In some embodiments, R¹⁰ is anunsubstituted C2, C3, C4 or C5 alkylene group having 2 separate pointsof attachment to different carbons, thus forming fused bicyclic rings,e.g., octahydroquinoxaline, 3,8-diazabicyclo[3.2.1]octane, and3,9-diazabicyclo[3.3.1]nonane. Thus, in some embodiments, the compoundsof formula I have the formulae IIA, IIB and IIC:

In some embodiments of the present compounds, R⁴ is CO₂H, CN, CONH₂,SO₂NH₂, or a substituted or unsubstituted CO₂—C₁-C₆ alkyl, CO₂—C₃-C₆cycloalkyl, CONH—C₁-C₆ alkyl, CONH—C₃-C₆ cycloalkyl, NH—SO₂—C₁-C₆ alkyl,or tetrazolyl group. In some embodiments, R⁴ is CO₂H, CN, CONH₂, or asubstituted or unsubstituted CO₂—C₁-C₆ alkyl, CONH—C₁-C₆ alkyl, ortetrazolyl group. In yet other embodiments, R⁴ is CO₂H, or anunsubstituted CO₂—C₁-C₆ alkyl, CONH₂, or tetrazolyl group. In someembodiments, R⁴ is CO₂H.

In the present compounds, X may be

It will be understood that as depicted, X is attached to R⁴ via the openvalence on the left side of the structure, and X is attached to thecentral nitrogen-containing heterocycle via the open valence on theright side of the structure.

In some embodiments, one of G¹, G², G³, and G⁴ is CR¹³ and the othersare CH (it being understood that R⁴ is attached in place of H at one ofthe G variables defined as CH). In other embodiments, one of G¹, G², G³,and G⁴ is CR¹³ and one is CR¹¹. In some embodiments, D is N and inothers, D is CR⁹. In some embodiments, Q is S. In others, Q is O, and instill others, Q is NR¹². In some embodiments, D is N and Q is S. Inothers, D is N and Q is NR¹². In some embodiments D is CR⁹ and Q is S,or D is CR⁹ and Q is NR¹².

Thus, in some embodiments, X is

wherein q is 0, 1, or 2. In some such embodiments, q is 0. In otherembodiments, q is 1. In the foregoing embodiments of X, R⁹, R¹¹, R¹² andR¹³ may have any of the values described herein for compounds of thepresent technology.

In some embodiments of the present compounds, R⁹ and R¹³ areindependently H, halo, or a substituted or unsubstituted C₁-C₄ alkyl, orO—(C₁-C₄ alkyl) group. In some embodiments, R⁹ is H, F, or Cl. In someembodiments, R¹³ is H, F, or a substituted or unsubstituted C₁-C₃ alkyl,or O—(C₁-C₃ alkyl) group. In some embodiments, R¹³ is H, F, CH₃, orOCH₃. In some embodiments, R⁹ is H.

In some embodiments, R¹¹ at each occurrence is independently halo, CF₃,or a substituted or unsubstituted alkyl or alkoxy group. In certainembodiments, R¹¹ is F, Cl, or CF₃. In some embodiments, R¹² is H or asubstituted or unsubstituted C₁-C₆ alkyl group. In some embodiments, R¹²is H or CH₃.

In some embodiments, Z is a substituted or unsubstituted C₁-C₄ alkyleneor O—C₁-C₄ alkylene group. In some embodiments, Z is a substituted orunsubstituted C₁-C₂ alkylene or O—C₁-C₂ alkylene group. In someembodiments, Z is a substituted or unsubstituted C₁-C₄ alkylene group.In some embodiments, Z is a substituted or unsubstituted C₁-C₂ alkylenegroup. In some embodiments, Z is a substituted or unsubstitutedmethylene, e.g., —CH₂—. In some embodiments, Z is a substituted orunsubstituted cyclopropylalkylene group. In some embodiments, Z may besubstituted with halo or OH. In some embodiments, Z may be substitutedwith F or OH. In some embodiments, Z may be substituted with F, OH, orCF₃.

In some embodiments, W is

In some embodiments of the present compounds, R¹ and R² areindependently halo, CN, CO₂R^(e), NR^(e)R^(f), or a substituted orunsubstituted C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ hydroxyalkyl group;and wherein R^(e) and R^(f) at each occurrence are independently H or asubstituted or unsubstituted C₁-C₆ alkyl group. In some embodiments, R¹and R² are independently H, F, Cl, CN, CO₂H, NR^(e)R^(f), or asubstituted or unsubstituted C₁-C₃ alkyl, C₁-C₃ alkoxy, or C₁-C₃hydroxyalkyl group. In some embodiments, R¹ and R² are independently H,F, Cl, CN, CO₂H, NH₂, CH₃, CH₂NH₂, OCF₃, or OCH₃. In some embodiments,R¹ and R² are both Cl. In some embodiments, one of R¹ and R² is H andthe other is OCF₃.

In some embodiments, R³ is a substituted or unsubstituted C₁-C₆ alkyl orC₃-C₆ cycloalkyl group. In some embodiments, R³ is CH₃, CH₂CH₃,CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₂CH₃)₂, CH(CH₂CH₃)(CH₃), C(CH₃)₃, orcyclopropyl. In some embodiments, R³ is an isopropyl or cyclopropylgroup.

In a third aspect, the present technology provides a compound accordingto formula IA, IB, or IC:

-   stereoisomers, and/or salts thereof; wherein-   L and M are independently N or CR⁷;-   Z is a substituted or unsubstituted C₁-C₄ alkylene, O—C₁-C₄    alkylene, cyclopropylalkylene, or oxetanylalkylene group;-   W is

-   X is

-   D is N or CR⁹;-   one of G¹, G², G³, and G⁴ is CR¹³ and the others are selected from    the group consisting of CH and CR¹¹;-   Q is O, S, or NR¹²;-   R¹ and R² are independently H, OH, halo, CN, carboxyl, NR^(a)R^(b),    or a substituted or unsubstituted alkyl, alkoxy, or hydroxyalkyl    group;-   R³ is a substituted or unsubstituted alkyl or cycloalkyl group;-   R⁴ is SO₃H, CONR^(a)R^(b), SO₂NR^(a)R^(b), NHSO₂R^(b), SO₂NHCOR^(a),    CO₂R^(c), or an unsubstituted tetrazolyl group;-   R⁷ is H, OH, halo, CN, carboxyl, amido, NR^(a)R^(b), or a    substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, or    aminoalkyl group;-   R⁹ and R¹³ are independently H, halo, or a substituted or    unsubstituted C₁-C₆ alkyl, or O—(C₁-C₆ alkyl) group;    -   R¹⁰ at each occurrence is independently halo, CO₂R^(c), or a        substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl,        cycloalkyl, or fluorinated cycloalkyl group, or, when n is 2 or        3, two of the R¹⁰ groups together may be a substituted or        unsubstituted C2-C5 alkylene or alkenylene group having 2        separate points of attachment to the same carbon or different        carbons of the nitrogen containing ring to which it is attached;-   R¹¹ is OH, halo, CF₃, CN, carboxyl, NR^(a)R^(b),or a substituted or    unsubstituted alkyl or alkoxy group;-   R¹² is H or a substituted or unsubstituted C₁-C₆ alkyl group; and-   R^(a) at each occurrence is independently H, or a substituted or    unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, or SO₂-alkyl    group;-   R^(b) at each occurrence is H or a substituted or unsubstituted    alkyl, or haloalkyl group;-   R^(c) is H or a substituted or unsubstituted alkyl, alkenyl, or    cycloalkyl group;-   n is 0, 1, 2, 3, or 4; and-   r and t are each independently 1, 2, or 3.

In an aspect of the present technology, a composition is provided thatincludes any one of the aspects and embodiments of compounds of formulasI-III and a pharmaceutically acceptable carrier. In a related aspect, apharmaceutical composition is provided which includes an effectiveamount of the compound of any one of the aspects and embodiments ofcompounds of formulas I-IV for treating an FXR-mediated disorder orcondition. The FXR-mediated disorder or condition may be liver disease,hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome,cardiovascular disease, gastrointestinal disease, atherosclerosis, orrenal disease. For example, the disorder or condition may be a liverdisease selected from the group consisting of primary biliary cirrhosis(PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosingcholangitis (PSC), nonalcoholic fatty liver disease (NAFLD),nonalcoholic steatohepatitis (NASH), liver fibrosis, and livercirrhosis.

In a further related aspect, a method is provided that includesadministering an effective amount of a compound of any one of theaspects and embodiments of compounds of formulas I-IV or administering apharmaceutical composition comprising an effective amount of a compoundof any one of the aspects and embodiments of compounds of formula I-IVto a subject suffering from an FXR-mediated disorder or condition. TheFXR-mediated disorder or condition may be liver disease, hyperlipidemia,hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease,gastrointestinal disease, atherosclerosis, or renal disease. In someembodiments, the disorder or condition is the disorder or condition maybe a liver disease selected from the group consisting of primary biliarycirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primarysclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD),nonalcoholic steatohepatitis (NASH), liver fibrosis, and livercirrhosis.

“Effective amount” refers to the amount of a compound or compositionrequired to produce a desired effect. One example of an effective amountincludes amounts or dosages that yield acceptable toxicity andbioavailability levels for therapeutic (pharmaceutical) use including,but not limited to, the treatment of hyperlipidemia. Another example ofan effective amount includes amounts or dosages that are capable ofreducing symptoms associated with metabolic syndrome, such as, forexample, obesity and/or metabolic syndrome. The effective amount of thecompound may selectively modulate FXR. As used herein, a “subject” or“patient” is a mammal, such as a cat, dog, rodent or primate. Typicallythe subject is a human, and, preferably, a human suffering from orsuspected of suffering from an FXR-mediated disorder or condition. Theterm “subject” and “patient” can be used interchangeably.

In still another aspect, the present technology provides methods ofmodulating FXR by contacting FXR with an effective amount of anycompound as described herein, including but not limited to a compound offormula I, II, III, or IV.

Thus, the instant present technology provides pharmaceuticalcompositions and medicaments comprising any of the compounds disclosedherein (e.g., compounds of formulas I-IV) and a pharmaceuticallyacceptable carrier or one or more excipients or fillers. Thecompositions may be used in the methods and treatments described herein.Such compositions and medicaments include a theapeutically effectiveamount of any compound as described herein, including but not limited toa compound of formula I, II, III, or IV. The pharmaceutical compositionmay be packaged in unit dosage form.

The pharmaceutical compositions and medicaments may be prepared bymixing one or more compounds of the present technology, stereoisomersthereof, and/or pharmaceutically acceptable salts thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like to prevent and treat disorders associated with the effects ofincreased plasma and/or hepatic lipid levels. The compounds andcompositions described herein may be used to prepare formulations andmedicaments that prevent or treat a variety of disorders associated withor mediated by FXR, including but not limited to liver disease,hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome,cardiovascular disease, gastrointestinal disease, atherosclerosis andrenal disease. Such compositions can be in the form of, for example,granules, powders, tablets, capsules, syrup, suppositories, injections,emulsions, elixirs, suspensions or solutions. The instant compositionscan be formulated for various routes of administration, for example, byoral, parenteral, topical, rectal, nasal, vaginal administration, or viaimplanted reservoir. Parenteral or systemic administration includes, butis not limited to, subcutaneous, intravenous, intraperitoneal, andintramuscular, injections. The following dosage forms are given by wayof example and should not be construed as limiting the instant presenttechnology.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant present technology, or pharmaceuticallyacceptable salts or tautomers thereof, with at least one additive suchas a starch or other additive. Suitable additives are sucrose, lactose,cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates,chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins,collagens, casein, albumin, synthetic or semi-synthetic polymers orglycerides. Optionally, oral dosage forms can contain other ingredientsto aid in administration, such as an inactive diluent, or lubricantssuch as magnesium stearate, or preservatives such as paraben or sorbicacid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, thickeners, buffers, sweeteners,flavoring agents or perfuming agents. Tablets and pills may be furthertreated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions, andsolutions, which may contain an inactive diluent, such as water.Pharmaceutical formulations and medicaments may be prepared as liquidsuspensions or solutions using a sterile liquid, such as, but notlimited to, an oil, water, an alcohol, and combinations of these.Pharmaceutically suitable surfactants, suspending agents, emulsifyingagents, may be added for oral or parenteral administration.

As noted above, suspensions may include oils. Such oils include, but arenot limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which may be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms may be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Typically, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation and/or medicament may be apowder suitable for reconstitution with an appropriate solution asdescribed above. Examples of these include, but are not limited to,freeze dried, rotary dried or spray dried powders, amorphous powders,granules, precipitates, or particulates. For injection, the formulationsmay optionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these.

Compounds of the present technology may be administered to the lungs byinhalation through the nose or mouth. Suitable pharmaceuticalformulations for inhalation include solutions, sprays, dry powders, oraerosols containing any appropriate solvents and optionally othercompounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. The carriers and stabilizers varywith the requirements of the particular compound, but typically includenonionic surfactants (Tweens, Pluronics, or polyethylene glycol),innocuous proteins like serum albumin, sorbitan esters, oleic acid,lecithin, amino acids such as glycine, buffers, salts, sugars or sugaralcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant)aerosols are typically used for delivery of compounds of the presenttechnology by inhalation.

Dosage forms for the topical (including buccal and sublingual) ortransdermal administration of compounds of the present technologyinclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, and patches. The active component may be mixed under sterileconditions with a pharmaceutically-acceptable carrier or excipient, andwith any preservatives, or buffers, which may be required. Powders andsprays can be prepared, for example, with excipients such as lactose,talc, silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder, or mixtures of these substances. The ointments, pastes, creamsand gels may also contain excipients such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Absorption enhancers can also be used toincrease the flux of the compounds of the present technology across theskin. The rate of such flux can be controlled by either providing a ratecontrolling membrane (e.g., as part of a transdermal patch) ordispersing the compound in a polymer matrix or gel.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instant presenttechnology. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

The formulations of the present technology may be designed to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

The instant compositions may also comprise, for example, micelles orliposomes, or some other encapsulated form, or may be administered in anextended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations and medicaments maybe compressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant present technology.

Those skilled in the art are readily able to determine an effectiveamount by simply administering a compound of the present technology to apatient in increasing amounts until for example, (for metabolic syndromeand/or obesity) the elevated plasma or elevated white blood cell countor hepatic cholesterol or triglycerides or progression of the diseasestate is reduced or stopped. For metabolic syndrome and/or obesity, theprogression of the disease state can be assessed using in vivo imaging,as described, or by taking a tissue sample from a patient and observingthe target of interest therein.

The compounds of the present technology can be administered to a patientat dosage levels in the range of about 0.1 to about 1,000 mg per day.For a normal human adult having a body weight of about 70 kg, a dosagein the range of about 0.01 to about 100 mg per kg of body weight per dayis sufficient. The specific dosage used, however, can vary or may beadjusted as considered appropriate by those of ordinary skill in theart. For example, the dosage can depend on a number of factors includingthe requirements of the patient, the severity of the condition beingtreated and the pharmacological activity of the compound being used. Thedetermination of optimum dosages for a particular patient is well knownto those skilled in the art.

Various assays and model systems can be readily employed to determinethe therapeutic effectiveness of the treatment according to the presenttechnology.

Effectiveness of the compositions and methods of the present technologymay also be demonstrated by a decrease in the symptoms ofhyperlipidemia, such as, for example, a decrease in triglycerides in theblood stream. Effectiveness of the compositions and methods of thepresent technology may also be demonstrated by a decrease in the signsand symptoms of liver disease, hyperlipidemia, hypercholesteremia,obesity, metabolic syndrome, cardiovascular disease, gastrointestinaldisease, atherosclerosis, or renal disease.

For each of the indicated conditions described herein, test subjectswill exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%,or 95% or greater, reduction, in one or more symptom(s) caused by, orassociated with, the disorder in the subject, compared toplacebo—treated or other suitable control subjects.

The compounds of the present technology can also be administered to apatient along with other conventional therapeutic agents that may beuseful in the treatment of liver disease, hyperlipidemia,hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease,gastrointestinal disease, atherosclerosis, or renal disease. Theadministration may include oral administration, parenteraladministration, or nasal administration. In any of these embodiments,the administration may include subcutaneous injections, intravenousinjections, intraperitoneal injections, or intramuscular injections. Inany of these embodiments, the administration may include oraladministration. The methods of the present technology can also compriseadministering, either sequentially or in combination with one or morecompounds of the present technology, a conventional therapeutic agent inan amount that can potentially be effective for the treatment of liverdisease, hyperlipidemia, hypercholesteremia, obesity, metabolicsyndrome, cardiovascular disease, gastrointestinal disease,atherosclerosis, or renal disease.

In one aspect, a compound of the present technology is administered to apatient in an amount or dosage suitable for therapeutic use. Generally,a unit dosage comprising a compound of the present technology will varydepending on patient considerations. Such considerations include, forexample, age, protocol, condition, sex, extent of disease,contraindications, concomitant therapies and the like. An exemplary unitdosage based on these considerations can also be adjusted or modified bya physician skilled in the art. For example, a unit dosage for a patientcomprising a compound of the present technology can vary from 1×10⁻⁴g/kg to 1 g/kg, preferably, 1×10⁻³g/kg to 1.0 g/kg. Dosage of a compoundof the present technology can also vary from 0.01 mg/kg to 100 mg/kg or,preferably, from 0.1 mg/kg to 10 mg/kg.

A compound of the present technology can also be modified, for example,by the covalent attachment of an organic moiety or conjugate to improvepharmacokinetic properties, toxicity or bioavailability (e.g., increasedin vivo half-life). The conjugate can be a linear or branchedhydrophilic polymeric group, fatty acid group or fatty acid ester group.A polymeric group can comprise a molecular weight that can be adjustedby one of ordinary skill in the art to improve, for example,pharmacokinetic properties, toxicity or bioavailability. Exemplaryconjugates can include a polyalkane glycol (e.g., polyethylene glycol(PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acidpolymer or polyvinyl pyrolidone and a fatty acid or fatty acid estergroup, each of which can independently comprise from about eight toabout seventy carbon atoms. Conjugates for use with a compound of thepresent technology can also serve as linkers to, for example, anysuitable substituents or groups, radiolabels (marker or tags), halogens,proteins, enzymes, polypeptides, other therapeutic agents (for example,a pharmaceutical or drug), nucleosides, dyes, oligonucleotides, lipids,phospholipids and/or liposomes. In one aspect, conjugates can includepolyethylene amine (PEI), polyglycine, hybrids of PEI and polyglycine,polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG). Aconjugate can also link a compound of the present technology to, forexample, a label (fluorescent or luminescent) or marker (radionuclide,radioisotope and/or isotope) to comprise a probe of the presenttechnology. Conjugates for use with a compound of the present technologycan, in one aspect, improve in vivo half-life. Other exemplaryconjugates for use with a compound of the present technology as well asapplications thereof and related techniques include those generallydescribed by U.S. Pat. No. 5,672,662, which is hereby incorporated byreference herein.

In another aspect, the present technology provides methods ofidentifying a target of interest including contacting the target ofinterest with a detectable or imaging effective quantity of a labeledcompound of the present technology. A detectable or imaging effectivequantity is a quantity of a labeled compound of the present technologynecessary to be detected by the detection method chosen. For example, adetectable quantity can be an administered amount sufficient to enabledetection of binding of the labeled compound to a target of interestincluding, but not limited to, a KOR. Suitable labels are known by thoseskilled in the art and can include, for example, radioisotopes,radionuclides, isotopes, fluorescent groups, biotin (in conjunction withstreptavidin complexation), and chemoluminescent groups. Upon binding ofthe labeled compound to the target of interest, the target may beisolated, purified and further characterized such as by determining theamino acid sequence.

The terms “associated” and/or “binding” can mean a chemical or physicalinteraction, for example, between a compound of the present technologyand a target of interest. Examples of associations or interactionsinclude covalent bonds, ionic bonds, hydrophilic-hydrophilicinteractions, hydrophobic-hydrophobic interactions and complexes.Associated can also refer generally to “binding” or “affinity” as eachcan be used to describe various chemical or physical interactions.Measuring binding or affinity is also routine to those skilled in theart. For example, compounds of the present technology can bind to orinteract with a target of interest or precursors, portions, fragmentsand peptides thereof and/or their deposits.

The examples herein are provided to illustrate advantages of the presenttechnology and to further assist a person of ordinary skill in the artwith preparing or using the compounds of the present technology orsalts, pharmaceutical compositions, derivatives, solvates, metabolites,prodrugs, racemic mixtures or tautomeric forms thereof. The examplesherein are also presented in order to more fully illustrate thepreferred aspects of the present technology. The examples should in noway be construed as limiting the scope of the present technology, asdefined by the appended claims. The examples can include or incorporateany of the variations, aspects or aspects of the present technologydescribed above. The variations, aspects or aspects described above mayalso further each include or incorporate the variations of any or allother variations, aspects or aspects of the present technology.

EXAMPLES List of Abbreviations

-   -   ACN acetonitrile    -   t-Bu tert-butyl    -   DCM dichloromethane    -   DIAD diisopropyl azodicarboxylate    -   DMF dimethylformamide    -   DMA dimethylacetamide    -   DMAP 4-dimethylaminopyridine    -   DMP tert-2,2-dimethoxypropane    -   DMSO dimethyl sulfoxide    -   Et ethyl    -   HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]        pyridinium 3-oxid hexafluorophosphate)    -   LAH lithium aluminum hydride    -   Me methyl    -   MeCN acetonitrile    -   NCS N-chlorosuccinimide    -   PCC pyridinium chlorochromate    -   PE petroleum ether    -   Ph phenyl    -   STAB sodium triacetoxyborohydride    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   TFAA trifluoroacetic anhydride    -   THF tetrahydrofuran    -   TLC thin layer chromatography    -   TMS trimethylsilyl    -   TsOH p-toluenesulfonic acid

Common Intermediates Synthetic Schemes

Experimental details for INT-001 (Scheme 1)

Methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate (Compound 1a): Toa solution of methyl 4-amino-3-methoxybenzoate (20 g, 110 mmol) inacetic acid (340 mL) was added NaSCN (35.8 g, 330 mmol) and Br₂ (26.2 g,165 mmol) sequentially. The mixture was stirred overnight at roomtemperature. The mixture was concentrated under vacuum. The residue wassuspended in 100 mL of water. The pH value of the mixture was adjustedto 8 with NaOH (2 M). The solids were collected and dried under vacuum.This resulted in 22.5 g of the title compound as a yellow solid (crudeproduct). LC-MS (ESI, m/z): [M+H]⁺=239.1.

Methyl 2-chloro-4-methoxybenzo[d]thiazole-6-carboxylate (CompoundINT-001): To a suspension of Compound 1a (22.5 g, 94 mmol) in MeCN (320mL) was added CuCl₂ (25 g, 188 mmol). The mixture was stirred for 5 minat room temperature before 3-methylbutyl nitrite (16.5 g, 141 mmol) wasadded dropwise at room temperature. The reaction was stirred for another1 h at 60° C. The reaction was then quenched by the addition of 60 mL ofwater. The resulting mixture was extracted with ethyl acetate severaltimes. The organic layers were combined. The organic phase was washedwith water and brine. The residue was concentrated under vacuum afterdried over anhydrous sodium sulfate. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 13 g (54%) of the title compound as a yellow solid. LC-MS(ESI, m/z): [M+H]⁺=258.2.

Following the procedure described above for Scheme 1 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following common intermediateswere prepared as shown in Table 1.

TABLE 1 LC-MS Compound Structure (M + H)⁺ INT-002

228.0 INT-003

242.3 INT-004

242.0 INT-005

242.3 INT-006

246.0 INT-007

246.3 INT-008

262.1

Experimental details for INT-011 (Scheme 2)

Methyl 2-mercaptobenzo[d]oxazole-6-carboxylate (Compound 2a): To astirring solution of methyl 4-amino-3-hydroxybenzoate (5 g, 29.91 mmol)in pyridine (60 mL) was added ethoxy(potassiosulfanyl)methanethione (5g, 31.19 mmol). The resulting solution was stirred for 5 h at 115° C.The reaction was quenched with water. The resulting solution wasextracted with 3'30 mL of dichloromethane. The organic layers werecombined and washed successively with water and brine. The residue wasconcentrated under vacuum after dried over anhydrous sodium sulfate.This resulted in 3.5 g (56%) of the title compound as a yellow solid.

Methyl 2-chlorobenzo[d]oxazole-6-carboxylate (Compound INT-011): To asuspension of Compound 2a (1 g, 4.78 mmol) in thionyl dichloride (5 mL)was added DMF (0.1 mL). The resulting solution was stirred for 15 min at80° C. The reaction solution was concentrated under vacuum. The crudewas diluted with DCM and washed successively with saturated NaHCO₃solution, water and brine. The residue was concentrated under vacuumafter dried over anhydrous sodium sulfate. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (23:77). Thisresulted in 520 mg (51%) of the title compound as a white solid.

Experimental details for INT-012 (Scheme 3)

Methyl 2-chloro-1H-indole-5-carboxylate (Compound 3a): To a solution ofphosphoryl trichloride (4 mL) was added methyl2-oxo-2,3-dihydro-1H-indole-5-carboxylate (500 mg, 2.62 mmol). Theresulting solution was stirred for 30 min at 50° C. The resultingsolution was diluted with 10 mL of ethyl acetate. The resulting solutionwas washed successively with water and brine. The residue wasconcentrated under vacuum after dried over anhydrous sodium sulfate. Thecrude product was applied onto a silica gel column with ethylacetate/petroleum ether (1:9). This resulted in 0.15 g (27%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=210.0.

Methyl 2-chloro-1-methyl-1H-indole-5-carboxylate (Compound INT-012): Toa solution of Compound 3a (150 mg, 0.72 mmol) in THF (5 mL) was addedsodium hydride (71 mg, 2.96 mmol) batchwise at 0° C. The mixture wasstirred for 30 min at room temperature then CH₃I (254 mg, 1.79 mmol) wasadded. The mixture was stirred for 6 h at room temperature. The reactionwas quenched by adding 5 mL of water. The resulting solution wasextracted with 3×5 mL of ethyl acetate and the organic layers werecombined. The resulted organic phase was washed successively with waterand brine. The residue was concentrated under vacuum after dried overanhydrous sodium sulfate. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 125mg (78%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=224.0.

Following the procedure described above for Scheme 3 and substitutingthe appropriate reagents, starting material and purification methodknown to those skilled in the art, the following common intermediate wasprepared.

TABLE 1I LC-MS Compound Structure (M + H)⁺ INT-013

225.0

Final Compounds Synthetic Schemes

Experimental details for Compound 11-03 (Scheme 4)

Methyl 2-[4-[(tert-butoxy) carbonyl]piperazin-1-yl]-4-methoxy-1,3-benzothiazole-6-carboxylate (Compound 4a):To a solution of methyl2-chloro-4-methoxy-1,3-benzothiazole-6-carboxylate (1 g, 3.88 mmol) inDMSO (10 mL) was added tert-butyl piperazine-1-carboxylate (720 mg, 3.87mmol) and potassium carbonate (800 mg, 5.79 mmol). The resultingsolution was stirred for 2 h at 120° C. The reaction was diluted withwater and extracted with 3×50 mL of dichloromethane. The organic layerswere combined and washed with water and brine, then dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 1.5 g of the title compound as a yellow solid. LC-MS (ESI):[M+H]⁺=408.2.

Methyl 4-methoxy-2-(piperazin-1-yl) benzo[d]thiazole-6-carboxylate(Compound 4b): To a solution of Compound 4a (1.5 g, 3.7 mmol) indichloromethane (10 mL) was added a solution of HCl in dioxane (10 mL,4M). The resulting solution was stirred for 2 h at room temperature. Thereaction mixture was concentrated under vacuum and the residue dissolvedin methanol. The pH value of the solution was adjusted to 6-7 withpotassium carbonate and the solids were filtered out. The resultingmixture was concentrated under vacuum. This resulted in 1.01 g of thetitle compound as a white solid. The resulted product used directlywithout further purification. LC-MS (ESI): [M+H]⁺=308.3.

Methyl2-(4-[[1-(2,6-dichlorophenyl)-4-(propan-2-yl)-1H-pyrazol-5-yl]methyl]piperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylate (Compound 4c):To a solution of Compound 4b (131 mg, 0.43 mmol) and1-(2,6-dichlorophenyl)-4-(propan-2-yl)-1H-pyrazole-5-carbaldehyde (100mg, 0.35 mmol) in dichloromethane (5 mL) was added NaOAc (96 mg, 0.71mmol). The mixture was stirred for 1 h at room temperature thenNaBH(OAc)₃ (300 mg, 1.42 mmol) was added. The resulting solution wasstirred overnight at room temperature. The mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:3). This resulted in 125 mg (51%) ofthe title compound as a white oil. LC-MS (ESI, m/z): [M+H]⁺=574.1.

2-(4-[[1-(2,6-Dichlorophenyl)-4-(propan-2-yl)-1H-pyrazol-5-yl]methyl]piperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylicacid (Compound II-03): To a solution of Compound 4c (80 mg, 0.14 mmol)in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL) wasadded a solution of sodium hydroxide (49 mg, 1.23 mmol) in water (1 mL).The resulting solution was stirred for 2 h at 50° C. The pH value of thesolution was adjusted to 5 with hydrogen chloride (2 N). The mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (15:1). This resulted in 27.1 mg(35%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=560.2. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 7.96 (s, 1H), 7.69-7.67(m, 3H), 7.58-7.54 (m, 1H), 7.40 (s, 1H), 3.87(s, 3H), 3.41 (s, 2H),3.34-3.36 (m, 4H), 3.01-2.94 (m, 1H), 2.34-2.31 (m, 4H), 1.23 (d, J=7.2Hz, 6H).

Experimental details for Compound II-07 (Scheme 5)

tert-Butyl3-[[1(tert-butyldiphenylsilyl)oxy]methyl]piperazine-1-carboxylate(Compound 5a): To a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1 g, 4.62 mmol) in dichloromethane (10 mL) wasadded 1H-imidazole (629 mg, 9.24 mmol). This was followed by addition ofa solution of TBDPSCl (1.18 mL, 1.30 mmol) in dichloromethane (10 mL)dropwise with stirring. The mixture was allowed warm to room temperatureand stirred for 3 h. The resulting solution was extracted with 3×50 mLof dichloromethane and the organic layers were combined. The resultingmixture was washed with 3x50 mL of sodium bicarbonate and 1×50 mL ofbrine. The resulting mixture was concentrated under vacuum after driedover anhydrous sodium sulfate. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (7:3). This resulted in 1.4 g(67%) of the title compound as a light yellow oil. LC-MS (ESI, m/z):[M+H]+=455.3.

Methyl2-[4-[(tert-butoxy)carbonyl]-2-[[(tert-butyldiphenylsilyl)oxy]methyl]piperazin-1-yl]-4-methoxy-1,3-benzothiazole-6-carboxylate(Compound 5b): To a solution of Compound 5a (455 mg, 1.0 mmol) in DMSO(10 mL) was added methyl2-chloro-4-methoxy-1,3-benzothiazole-6-carboxylate (223 mg, 0.87 mmol)and potassium carbonate (207 mg, 1.50 mmol). After stirring for 3 h at120° C., the resulting mixture was diluted with ethyl acetate (100 mL).The resulted mixture was washed with water and brine. The residue wasconcentrated under vacuum after dried over anhydrous sodium sulfate. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:4). This resulted in 300 mg (44%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]+=676.2.

Methyl2-(2-[[(tert-butyldiphenylsilyl)oxy]methyl]piperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylate(Compound 5c): To a solution of Compound 5b (300 mg, 0.44 mmol) indioxane (5 mL) was added a solution of hydrogen chloride in dioxane (5mL, 4M). After stirring for 1 h at room temperature, the resultingmixture was concentrated under vacuum. The resulted solids were washedwith ethyl acetate and dried under vacuum. This resulted in 120 mg (47%)of the title compound as a light yellow oil. LC-MS (ESI, m/z):[M+H]⁺=576.3.

Methyl2-(2-[[(tert-butyldiphenylsilyl)oxy]methyl]-4-[[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]piperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylate(Compound 5d): To a solution of Compound 5c (100 mg, 0.17 mmol) and3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole-4-carbaldehyde (49.39mg, 0.17 mmol) in dichloromethane (5 mL) was added sodium acetate (14.6mg, 0.18 mmol). After stirring for 30 min, NaBH(OAc)₃ (111 mg, 0.52mmol) was added. The resulting solution was stirred for 16 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:4). This resulted in 72.4 mg (49%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=843.1.

Methyl2-(4-[[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]-2-(hydroxymethyl)piperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylate(Compound 5e): To a solution of Compound 5d (70 mg, 0.08 mmol) inethanol (10 mL) was added hydrogen chloride (2 mL, 6M). The resultingsolution was stirred for 16 h at room temperature. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(2:1). This resulted in 30 mg (60%) of the title compound as a whitesolid. LC-MS (ESI, m/z): [M+H]⁺=605.2.

2-(4-[[3-(2,6-Dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]-2-(hydroxymethyl)piperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylicacid (Compound II-07): Into a 25-mL round-bottom flask, was placed asolution of Compound 5e (100 mg, 0.17 mmol) in methanol (4 mL), then asolution of sodium hydroxide (64 mg, 1.60 mmol) in water (2 mL) wasadded. After stirring for 2 h at 50° C., the mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withCH₃CN/H₂O (4:1). This resulted in 16.1 mg (16%) of the title compound asa white solid. LC-MS (ESI, m/z): [M+H]⁺=591.3. ¹H-NMIR (300 MHz, CDCl₃,ppm): δ 7.99 (s, 1H), 7.67-7.51 (m, 4H), 4.62-4.22 (m, 5H), 4.04 (s,3H), 3.93-3.68 (m, 3H), 3.37-3.33 (m, 1H), 2.88-2.73 (m, 3H), 1.48 (brs,6H).

Experimental details for Compound II-22 (Scheme 6)

tert-Butyl4-[[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]-3,3-dimethylpiperazine-1-carboxylate(Compound 6a): To a solution of tert-butyl3,3-dimethylpiperazine-1-carboxylate (150 mg, 0.70 mmol) indichloromethane (5 mL) was added3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole-4-carbaldehyde (180mg, 0.63 mmol) and sodium acetate (87 mg, 1.06 mmol). The mixture wasstirred for 1 h at room temperature. Then STAB (404 mg, 1.91 mmol) wasadded. The resulting solution was stirred overnight at room temperature.The reaction was then quenched by adding water (15 mL). The resultingmixture was extracted with 5×5 mL of dichloromethane and the organiclayers were combined. The organic phase was washed successively withwater and brine. The residue was concentrated under vacuum after driedover anhydrous sodium sulfate. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 0.116g (38%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=482.4.

1-[[3-(2,6-Dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]-2,2-dimethylpiperazine(Compound 6b): To a solution of Compound 6a (116 mg, 0.24 mmol) indioxane was added a solution of hydrogen chloride in dioxane (3 mL, 4M).The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 0.09 g(98%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=382.1.

Methyl2-(4-[[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]-3,3-dimethylpiperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylate(Compound 6c): To a solution of methyl2-chloro-4-methoxy-1,3-benzothiazole-6-carboxylate (88 mg, 0.34 mmol) inDMSO (3 mL) was added Compound 6b (90 mg, 0.24 mmol) and potassiumcarbonate (107 mg, 0.77 mmol). The resulting solution was stirred for 3h at 120° C. The reaction was then quenched by the addition of water (5mL). The resulting solution was extracted with 5×5 mL of ethyl acetateand the organic layers were combined. The organic phase was washedsuccessively with water and brine. The residue was concentrated undervacuum after dried over anhydrous sodium sulfate. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:3). This resulted in 0.11 g (77%) of the title compound as a whitesolid. LC-MS (ESI, m/z): [M+H]⁺=603.2.

2-(4-[[3-(2,6-Dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]-3,3-dimethylpiperazin-1-yl)-4-methoxy-1,3-benzothiazole-6-carboxylicacid (Compound II-22): To a solution of Compound 6c (110 mg, 0.18 mmol)in a mixed solvent of methanol/tetrahydrofuran/water (3 mL, 1:1:1) wasadded sodium hydroxide (37 mg, 0.93 mmol). The resulting solution wasstirred for 2 h at 50° C. The pH value of the solution was adjusted to 5with hydrogen chloride (2 N). The mixture was concentrated under vacuum.The residue was applied onto a silica gel column withdichloromethane/methanol (15:1). This resulted in 0.05 g (47%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=589.2. ¹H NMR(400 MHz, DMSO-d₆, ppm): δ 7.96 (d, J=1.6 Hz, 1H), 7.64-7.62 (m, 2H),7.57-7.53 (m, 1H), 7.38 (d, J=1.2 Hz, 1H), 3.88 (s, 3H), 3.48 (s, 2H),3.39-3.27 (m, 3H), 3.00 (s, 2H), 2.44-2.42 (m, 2H), 1.33-1.30 (d, J=6.8Hz, 6H), 0.75 (s, 6H).

Experimental Details for Compound II-45 (Scheme 7)

(R)-tert-Butyl2-methyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(Compound 7a): To a solution of N-[(1,1-difluoroethane)sulfinyl]-1,1,1-trifluoro-N-phenylmethanesulfinamide (213 mg, 1.0 mmol)in THF (3 mL) was added HMDSLi (1.1 mL, 1.1mmol) dropwise at −78° C.under N₂ atmosphere. The mixed was stirred for 30 min at −78° C., then asolution of tert-butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate (393mg, 1.1 mmol) in THF (2 mL) was added dropwise. The resulting mixturewas stirred for 2 h at −78° C. The reaction was then quenched by theaddition of 5 mL of water. The resulting solution was diluted with ethylacetate. The resulted mixture was washed with water and brine. Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 300 mg of the title compound as a colorless oil(crude product).

(R)-tert-Butyl2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(Compound 7b): To a solution of4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(100 mg, 0.39 mmol) in dioxane (2 mL) was added Compound 7a (110 mg,0.32 mmol), Pd(dppf)Cl₂ (66 mg, 0.09 mmol) and potassium acetate (81 mg,0.83 mmol). The mixture was stirred overnight at 80° C. under N₂atmosphere. The resulting mixture was diluted with ethyl acetate. Theresulted mixture was washed with water and brine. The residue was driedover anhydrous sodium sulfate and concentrated under vacuum. The crudeproduct was applied onto a silica gel column with ethylacetate/petroleum ether (27:73). This resulted in 100 mg (79%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=324.2.

4-(Chloromethyl)-3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole(Compound 7c): To a solution of[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl] methanol (500mg, 1.75 mmol) in dichloromethane (5 mL) was added sulfurous dichloride(225 mg, 1.89 mmol) and DMF (0.5 mL). The resulting solution was stirredfor 1 h at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:9). This resulted in 460 mg (86%) ofthe title compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=304.3.

(R)-tert-Butyl 4-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)methyl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Compound 7d): Toa solution of Compound 7b (240 mg, 0.74 mmol) and Compound 7c (150 mg,0.49 mmol) in dioxane (4 mL) was added tetrakis(triphenylphosphane)palladium (58 mg, 0.05 mmol), sodium carbonate (159 mg, 1.49 mmol) andwater (1 mL). The resulting solution was stirred for 4 h at 80° C. underN₂ atmosphere. The mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(23:77). This resulted in 80 mg (35%) of the title compound as a yellowoil. LC-MS (ESI, m/z): [M+H]⁺=465.4.

(2R)-tert-Butyl 4-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)methyl)-2-methylpiperidine-1-carboxylate (Compound 7e): To a solution ofCompound 7d (150 mg, 0.32 mmol) in ethyl acetate (3 mL) was added PtO₂(22.7 mg, 0.10 mmol). The mixed was stirred overnight at roomtemperature under H₂ atmosphere. The solids were filtered out. Theresulting mixture was concentrated under vacuum. This resulted in 120 mg(80%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=467.0.

3-(2,6-Dichlorophenyl)-5-isopropyl-4-(((2R)-2-methylpiperidin-4-yl)methyl) isoxazole (Compound 7f): To a solution of Compound 7e (120 mg,0.26 mmol) in dioxane (3 mL) was added a mixture of hydrogen chloride indioxane (5 mL, 4M). The mixture was stirred for 1 h at room temperaturethen concentrated under vacuum. This resulted in 70 mg (74%) of thetitle compound as a yellow solid. LC-MS (ESI, m/z): [M+H]⁺=367.0.

Methyl 2-((2R)-4-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)methyl)-2-methylpiperidin-1-yl)-4-methoxybenzo[d]thiazole-6-carboxylate(Compound 7g): To a solution of methyl2-chloro-4-methoxy-1,3-benzothiazole-6-carboxylate (70 mg, 0.27 mmol) inDMSO (3 mL) was added Compound 7f (99 mg, 0.27 mmol) and potassiumcarbonate (112 mg, 0.80 mmol). The mixture was stirred for 2 h at 120°C. The reaction was then quenched by the addition of water. Theresulting solution was diluted with EA. The resulting mixture was washedwith water and brine. The mixture was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (25:75). Thisresulted in 70 mg (44%) of the title compound as a yellow solid. LC-MS(ESI, m/z): [M+H]⁺=588.2.

2-((2R)-4-((3-(2,6-Dichlorophenyl)-5-isopropylisoxazol-4-yl)methyl)-2-methylpiperidin-1-yl)-4-methoxybenzo[d]thiazole-6-carboxylicacid (Compound II-45): To a solution of Compound 7g (70 mg, 0.12 mmol)in a mixture of THF (1 mL), water (1 mL) and methanol (1 mL) was addedsodium hydroxide (24 mg, 0.60 mmol). The resulting solution was stirredfor 1 h at 50° C. The pH value of the solution was adjusted to 6 withhydrogen chloride (2 M). The solids were filtered out. The reactionmixture was concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions: Column, SunFire Prep C18 OBDColumn, 19*150mm, Sum; mobile phase: Water (0.1% TFA) and ACN (60% ACNup to 67% in 10 min); Detector, UV 254/220 nm. This resulted in 3.9 mg(6%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=573.7. ¹HNMR (400 MHz, DMSO-d₆, ppm): δ 7.94 (s, 1H), 7.71-7.69(m, 2H), 7.63-7.59 (m, 1H), 7.39 (s, 1H), 4.35 (s, 1H), 3.87 (s, 3H),3.31-3.23 (m, 2H), 3.10-3.04 (m, 1H), 2.34-2.26 (m, 1H), 2.19-2.10 (m,1H), 1.63-1.45 (m, 3H), 1.33-1.24 (m, 7H), 1.16-1.08 (m, 1H), 1.05-1.03(d, J=6.8 Hz, 3H).

Experimental details for Compound II-47 (Scheme 8)

Methyl2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-methoxybenzo[d]thiazole-6-carboxylate(Compound 8a): To a solution of methyl2-chloro-4-methoxy-1,3-benzothiazole-6-carboxylate (300 mg, 1.16 mmol)and tent-butyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(543 mg, 1.76 mmol) in a mixed solvent of dioxane (4 mL) and water (1mL) was added Pd(dppf)Cl₂ (87.7 mg, 0.12 mmol) and sodium carbonate (372mg, 3.51 mmol). The resulting solution was stirred for 3 h at 80° C.under N2 atmosphere. The filtrate was concentrated under vacuum afterfiltration. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (21:79). This resulted in 340 mg (72%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=405.2

Methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methoxybenzo[d]thiazole-6-carboxylate (Compound 8b):To a solution of Compound 8a (340 mg, 0.84 mmol) in ethyl acetate (6 mL)was added PtO₂ (76 mg, 0.33 mmol). The resulting solution was stirredovernight at 30° C. under H₂ atmosphere. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (28:72). Thisresulted in 250 mg (73%) of the title compound as a white solid. LC-MS(ESI, m/z): [M+H]+=407.2.

Methyl 4-methoxy-2-(piperidin-4-yl) benzo[d]thiazole-6-carboxylate(Compound 8c): Into a 50-mL round-bottom flask was placed Compound 8b(250 mg, 0.62 mmol, 1.00 equiv), hydrogen chloride/dioxane (10 mL). Theresulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 180 mg(96%) of the title compound as a white solid. LC-MS (ES, m/z):[M+H]+=307.1.

Methyl 2-(1-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl) methyl)piperidin-4-yl)-4-methoxybenzo[d]thiazole-6-carboxylate (Compound 8d):To a solution of Compound 8b (135 mg, 0.44 mmol), and3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole-4-carbaldehyde (125mg, 0.44 mmol) in dichloromethane (3 mL) was added sodium acetate (37mg, 0.45 mmol). The mixture was stirred for 30 min then NaBH(OAc)₃ (280mg, 1.32 mmol) was added. The resulting solution was stirred overnightat room temperature. The solids were filtered out. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(32:68). This resulted in 130 mg (51%) of the title compound ascolorless oil. LC-MS (ESI, m/z): [M+H]⁺=574.3.

2-(1-((3-(2,6-Dichlorophenyl)-5-isopropylisoxazol-4-yl) methyl)piperidin-4-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (CompoundII-47): To a solution of Compound 8d (130 mg, 0.23 mmol) in a mixedsolvent of THF (1 mL) and methanol (1 mL) was added a solution of sodiumhydroxide (45 mg, 1.13 mmol) in water (0.5 mL). The resulting solutionwas stirred for 1 h at 50° C. The pH value of the solution was adjustedto 6 with hydrogen chloride (2 N). The resulting mixture wasconcentrated under vacuum. The residue was applied onto a C18 columnwith H₂O/CH₃CN (35:65). This resulted in 35.7 mg (28%) of the titlecompound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=560.0. HNMR (300MHz, DMSO-d₆, ppm): δ 8.25 (s, 1H), 7.59 (s, 1H), 7.42-7.38 (m, 3H),4.12 (s, 3H), 3.29 (brs, 3H), 3.15 (brs, 1H), 2.89 (brs, 2H), 2.09-1.85(m, 4H), 1.75-1.56 (m, 2H), 1.43 (d, J=6.6 Hz, 6H).

Experimental details for Compound VII-04 (Scheme 9)

5-Bromo-7-(trifluoromethoxy) benzo[d]thiazol-2-amine (Compound 9a): To asolution of 4-bromo-2-(trifluoromethoxy) aniline (5.00 g, 19.53 mmol) inacetic acid (60 mL) was added NaSCN (6.33 g,78.12 mmol) batchwise atroom temperature. The mixture was stirred for 30 min then a solution ofBr₂ (6.24 g, 39.0 mmol) in acetic acid (10 mL). The resulting mixturewas stirred for 8 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was suspended in water. The pHvalue of the mixture was adjusted to 9 with solid Na₂CO₃. The solidswere collected by filtration and washed with water, dried under vacuum.This resulted in 5.70 g (93%) of the title compound as an orange solid(crude product). LC-MS (ESI, m/z): [M+H]⁺=315.

5-Bromo-2-chloro-7-(trifluoromethoxy) benzo[d]thiazole (Compound 9b): Toa suspension of Compound 9a (4.40 g, 14.05 mmol) in MeCN (60 mL) wasadded CuCl₂ (3.77 g, 28.02 mmol). The mixture was stirred for 30 minbefore 3-methylbutyl nitrite (2.47 g, 21.10 mmol) was added dropwise atroom temperature. The resulting mixture was stirred for 8 h at roomtemperature. The solid was filtrated out, the resulted filtrate wasdiluted with ethyl acetate. The mixture was washed with water and brine.The resulting mixture was concentrated under vacuum after dried overanhydrous sodium sulfate. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:3). This resulted in 840 mg(18%) of the title compound as a light yellow solid.

(R)-4-((4-(6-Bromo-4-(trifluoromethoxy)benzo[d]thiazol-2-yl)-3-methylpiperazin-1-yl)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) isoxazole (Compound 9c): Toa solution of Compound 9b (150 mg, 0.45 mmol) in DMSO (5 mL) was addedK₂CO₃ (62.1 mg, 0.45 mmol) and (3R)-1-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methyl]-3-methylpiperazine (110mg, 0.30 mmol). The mixture was stirred for 12 h at 120° C. The mixturewas diluted with water. The mixture was extracted with ethyl acetateseveral times. The organic layers were combined and washed with waterand brine. The residue was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:3). This resulted in 160 mg(79%) of the title compound as an off-white solid. LC-MS (ESI, m/z):[M+H]⁺=663.3.

(R)-Methyl 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl) isoxazol-4-yl)methyl)-2-methylpiperazin-1-yl)-4-(trifluoromethoxy)benzo[d]thiazole-6-carboxylate (Compound 9d): To a solution of Compound9c (160 mg, 0.24 mmol) and triethylamine (1.5 mL) in methanol (5 mL) wasadded Pd(dppf)Cl₂ (20 mg, 0.027 mmol). The mixture was stirred for 48 hat 80° C. under CO (20 atm). The solid was filtered out after cooling toroom temperature. The filtrate was concentrated and applied onto asilica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 120 mg (77%) of the title compound as an off-white solid.LC-MS (ESI, m/z): [M+H]⁺=641.0.

2-[(2R)-4-[[5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methyl]-2-methylpiperazin-1-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylicacid (Compound VII-04): To a solution of Compound 9d (120 mg, 0.19 mmol)in methanol (4 mL) was added a solution of sodium hydroxide (50 mg) inwater (2 mL). The mixture was stirred for 4 h at 50° C. The pH of themixture was adjusted to 2 with HCl (2M). The residue was extracted withethyl acetate several times. The organic layers were combined andconcentrated under vacuum after dried over anhydrous sodium sulfate. Thecrude product was purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XSelect CSH Prep C18 OBDColumn, 5 um,19*150 mm; mobile phase, Water (0.05% HCl) and ACN (60% ACNup to 85% in 7 min); Detector, UV 254/220 nm. This resulted in 3.1 mg(3%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=627.0. ¹HNMR (400 MHz, DMSO-d₆, ppm): δ 8.23 (s, 1H), 7.91 (s,1H), 7.44-7.36 (m, 2H), 7.34-7.32 (m, 1H), 4.33-3.75 (brs, 2H),3.50-3.23 (m, 3H), 2.97-2.88 (m, 1H), 2.69-2.58 (m, 1H), 2.39-2.31 (m,1H), 2.25-2.18 (m, 1H), 2.03-1.95 (m, 1H), 1.32-1.25 (m, 2H), 1.18-1.02(m, 5H).

Experimental details for Compound II-46 (Scheme 10)

4-(Chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole(Compound 10a): To a solution of[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl] methanol (1 g,3.52 mmol) in DCM (7 mL) was added SOCl₂(460 mg, 3.87 mmol) and DMF (2drops). The resulting solution was stirred for 1 h at room temperature.The reaction was quenched by the addition of water. The resultingmixture was diluted with DCM and washed with water and brine. Themixture was dried over anhydrous sodium sulfate. The mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:5). This resulted in 1 g(94%) of the title compound as an orange oil. LCMS (ESI, m/z):[M+H]⁺=302.1.

(R)-tert-Butyl 4-((3-(2,6-dichlorophenyl)-5-cyclopropylisoxazol-4-yl)methyl)-5,6-dihydro-6-methylpyridine-1(2H)-carboxylate (Compound 10b):To a solution oftert-butyl(2R)-2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate((220 mg, 0.68 mmol) in a mixture of dioxane (3 mL) and H₂O (1 mL) wasadded Compound 10a (280 mg, 0.93 mmol), Pd(PPh₃)₄ (20 mg, 0.02 mmol) andNa₂CO₃ (231 mg, 2.16 mmol). The resulting solution was stirred for 3 hat 80° C. under N₂ atmosphere. The mixture was diluted with ethylacetate and washed with water and brine. The mixture was concentratedunder vacuum after dried over anhydrous sodium sulfate. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:4). This resulted in 80 mg (crude product) of the title compound asan orange oil. LCMS (ESI, m/z): [M+H]⁺=463.3.

(2R)-4-[[5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methyl]-2-methyl-1,2,3,6-tetrahydropyridine(Compound 10c): To a solution of Compound 10b (50 mg, 0.11 mmol) indioxane (4 mL) was added a solution of hydrogen chloride in dioxane (6mL, 4M). The resulting solution was stirred for 1 h at room temperature.The mixture was concentrated under vacuum. This resulted in 35 mg (89%)of the title compound as a light yellow oil. LCMS (ESI, m/z):[M+H]⁺=363.2.

Methyl2-[(2R)-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methyl]-2-methyl-1,2,3,6-tetrahydropyridin-1-yl]-4-methoxy-1,3-benzothiazole-6-carboxylate(Compound 10d): To a solution of methyl2-chloro-4-methoxy-1,3-benzothiazole-6-carboxylate (100 mg, 0.33 mmol)in DMSO (3 mL) was added K₂CO₃ (138 mg, 0.99 mmol) and Compound 10c (120mg, 0.33 mmol). The resulting solution was stirred for 3 h at 120° C.The reaction was quenched by the addition of water. The resultingmixture was extracted with ethyl acetate several times. The organiclayers were combined and washed with water and brine. The residue wasdried over anhydrous sodium sulfate. The mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 50 mg (26%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): [M+H]⁺=584.2.

2-[(2R)-4-[[5-Cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methyl]-2-methyl-1,2,3,6-tetrahydropyridin-1-yl]-4-methoxy-1,3-benzothiazole-6-carboxylicacid (Compound II-46): To a solution of Compound 10d (30 mg, 0.05 mmol)in a mixture of methanol (1 mL) and tetrahydrofuran (1 mL) was added asolution of sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). Theresulting solution was stirred for 2 h at 50° C. The pH value of thesolution was adjusted to 6-7 with hydrogen chloride (2 N). The resultingmixture was concentrated under vacuum. The residue was applied onto areversed column with ACN: H₂O (4:6). This resulted in 2 mg (7%) of thetitle compound as a white solid. LCMS (ESI, m/z): [M+H]⁺=570.3. ¹HNMR(400 MHz, DMSO-d₆, ppm): δ 8.00-7.98 (m, 1H), 7.64-7.52 (m, 3H), 7.38(s, 1H), 5.15 (s, 1H), 5.03 (s, 1H), 4.30 (s, 1H), 3.97 (s, 3H),3.22-2.97 (m, 3H), 2.29-2.25 (m, 1H), 2.18-2.12 (m, 1H),1.90-1.78 (m,1H), 1.13-1.06 (m, 7H).

Experimental details for Compound VII-01 (Scheme 11)

(R)-Methyl2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-4-chlorobenzo[d]thiazole-6-carboxylate(Compound 11a): To a solution of methyl2,4-dichloro-1,3-benzothiazole-6-carboxylate (50 mg, 0.19 mmol) in DMSO(2 mL) was added tert-butyl (3R)-3-methylpiperazine-1-carboxylate (38mg, 0.19 mmol) and potassium carbonate (79 mg, 0.57 mmol). The mixturewas stirred for 2 h at 120° C. The reaction solution was diluted withethyl acetate. The resulted mixture was washed with water and brine. Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (27:73). This resulted in 30 mg (37%) of thetitle compound as a white solid. LCMS (ESI, m/z): [M+H]⁺=426.3.

(R)-Methyl2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-4-(prop-1-en-2-yl)benzo[d]thiazole-6-carboxylate (Compound 11b): To a solution of Compound11a (30 mg, 0.07 mmol) in dioxane (1 mL) was added potassiumisopropenyltrifluoroborate (31 mg, 0.21 mmol), Pd₂(dba)₃.CHCl₃ (4 mg,0.005 mmol), dppf (4 mg, 0.01 mmol) and cesium carbonate (69 mg, 0.21mmol). The mixture was stirred for 3 hat 150° C. under N₂ atmosphere.The mixture was diluted with ethyl acetate and further washed with waterand brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:4). This resulted in 30 mg(crude) of the title compound as a solid. LCMS (ESI, m/z): [M+H]⁺=432.0

(R)-Methyl2-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-4-isopropylbenzo[d]thiazole-6-carboxylate(Compound 11c): To a solution of Compound 11b (30 mg, 0.07 mmol) inmethanol (2 mL) was added Pd-C (15 mg, 10%, w %). The mixture solutionwas stirred for 2 h at room temperature under H₂ atmosphere. Thefiltrate was concentrated under vacuum after filtration. This resultedin 28 mg (93%) of the title compound as a white solid. LCMS (ESI, m/z):[M+H]⁺=434.2.

(R)-Methyl 4-isopropyl-2-(2-methylpiperazin-1-yl)benzo[d]thiazole-6-carboxylate (Compound 11d): To a solution of Compound11c (30 mg, 0.07 mmol) in dioxane (2 mL) was added a solution ofhydrogen chloride in dioxane (2 mL, 4M). The mixture was stirred for 1 hat room temperature. The mixture was concentrated under vacuum. Thisresulted in 20 mg (87%) of the title compound. LCMS (ESI, m/z):[M+H]⁺=334.2.

(R)-Methyl 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl) isoxazol-4-yl)methyl)-2-methylpiperazin-1-yl)-4-isopropylbenzo[d]thiazole-6-carboxylate(Compound 11e): To a solution of Compound 11d (20 mg, 0.06 mmol) indichloromethane (1 mL) was added5-cyclopropyl-3-(2,6-dichlorophenyl)-4,5-dihydro-1,2-oxazole-4-carbaldehyde(20 mg, 0.07 mmol) and sodium acetate (6 mg, 0.07 mmol). The mixed wasstirred for 30 min at room temperature then NaBH(OAc)₃ (40 mg, 0.24mmol) was added. The reaction was stirred overnight at room temperature.The resulting mixture was diluted with DCM and washed with water andbrine. The residue was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:3). This resulted in 35 mg(97%) of the title compound as a white solid. LCMS (ESI, m/z):[M+H]⁺=599.3.

(R)-2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl) isoxazol-4-yl)methyl)-2-methylpiperazin-1-yl)-4-isopropylbenzo[d]thiazole-6-carboxylicacid (Compound VII-01): To a solution of Compound 11e (35 mg, 0.06 mmol)in a mixed solution of THF (1 mL), methanol (1 mL) and water (1 mL) wasadded sodium hydroxide (12 mg, 0.30 mmol). The resulting mixture wasstirred for 1 h at 50° C. The pH value of the solution was adjusted to 6with hydrogen chloride (2 N). The mixture was concentrated under vacuum.The residue was applied onto a C18 gel column with ACN/H₂O (62:38). Thisresulted in 6.8 mg (20%) of the title compound as a white solid. LCMS(ESI, m/z): [M+H]⁺=585.1. ¹HNMR (400 MHz, DMSO-d₆, ppm): δ 8.18-8.17 (m,1H), 7.83-7.72 (m, 1H), 7.66-7.64 (m, 2H), 7.57-7.55 (m, 1H), 4.18-4.17(m, 1H), 3.79-3.78 (m, 1H), 3.56-3.51 (m, 1H), 3.29-3.17 (m, 3H),2.82-2.79 (m, 1H), 2.68-2.60 (m, 1H), 2.38-2.34 (m, 1H), 2.28-2.24 (m,1H), 1.97-1.92 (m, 1H), 1.27-1.25 (m, 6H), 1.18-1.09 (m, 4H), 0.98-0.95(m, 3H).

Following the procedure described above for Scheme 4-9 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

TABLE 2

LC-MS ¹HNMR Compound A* B Scheme (M + H)⁺ (ppm) II-01

4 561.2 CD₃OD-d₄: δ 8.05 (s, 1H), 7.68-7.54 (m, 4H), 4.25 (s, 2H), 4.02(s, 3H), 3.62-3.60 (m, 1H), 3.34-3.32 (m, 8H), 1.49 (d, J = 6.9 Hz, 6H).II-02

4 559.2 DMSO-d₆: δ 7.99 (s, 1H), 7.65-7.62 (m, 2H), 7.58-7.53 (m, 1H),7.39 (d, J = 1.2 Hz, 1H), 3.89 (s, 3H), 3.40 (brs, 4H), 3.34 (s, 2H),2.38-2.34 (m, 5H), 1.18-1.09 (m, 4H). II-04

4 562.1 DMSO-d₆: δ 12.75 (s, 1H), 8.83 (m, 2H), 7.99 (m, 1H), 7.38 (s,1H), 3.88 (s, 3H), 3.52-3.34 (m, 7H), 2.36 (s, 4H), 1.35-1.33 (d, J =7.2 Hz, 6H). II-05

4 577.3 DMSO-d₆: δ 12.75 (s, 1H), 7.99 (s, 1H), 7.71-7.64 (m, 2H),7.55-7.53 (m, 2H), 7.38 (s, 1H), 3.88 (s, 3H), 3.56- 3.32 (m, 7H), 2.35(brs, 4H), 1.34-1.23 (d, J = 6.8 Hz, 6H). II-06

4 574.9 DMSO-d₆: δ 7.97 (s, 1H), 7.73-7.71 (m, 1H), 7.67-7.65 (m, 1H),7.63-7.54 (m, 2H), 7.38 (s, 1H), 3.87 (s, 3H), 3.40-3.32 (m, 6H),2.37-2.33 (m, 5H), 1.14-1.07 (m, 4H). II-08

4 575.1 DMSO-d₆,: δ 12.68 (brs, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.66-7.63(m, 2H), 7.57-7.51 (m, 1H), 7.37 (d, J = 1.5 Hz, 1H), 4.12 (brs, 1H),3.87 (s, 3H), 3.74-3.70 (m, 1H), 3.38- 3.34 (m, 1H), 3.21-3.16 (m, 3H),2.78-2.73 (m, 1H), 2.57- 2.55 (m, 1H), 2.23-2.18 (m, 1H), 1.87-1.86 (m,1H), 1.36- 1.32 (m, 6H), 0.93-0.91 (d, J = 6.6 Hz, 3H). II-09

4 573.3 CD₃OD-d₄: δ 7.98 (s, 1H), 7.57-7.46 (m, 4H), 4.24 (brs, 1H),3.99 (s, 3H), 3.88-3.84 (m, 1H), 3.34 (s, 2H), 2.93- 2.90 (m, 1H), 3.66(d, J = 10.8 Hz, 1H), 2.35-2.29 (m, 2H), 2.04-1.94 (m, 2H), 1.19 (t, J =2 Hz, 4H), 1.08 (d, J = 7.8 Hz, 3H). II-10

4 575.2 DMSO-d₆: δ 12.73 (s, 1H), 7.98 (s, 1H), 7.66-7.63 (m, 2H),7.57-7.52 (m, 1H), 7.37 (s, 1H), 4.20-4.10 (m, 1H), 3.88 (s, 3H),3.80-3.68 (m, 1H), 3.42-3.35 (m, 1H), 3.25- 3.1 (m, 3H), 2.81-2.72 (m,1H), 2.60-2.55 (m, 1H), 2.25- 2.15 (m, 1H), 1.92-1.80 (m, 1H), 1.40-1.30(m, 6H), 0.93 (d, J = 6.6 Hz, 3H). II-11

4 573.2 DMSO-d₆: δ 12.75 (s, 1H), 8.00 (s, 1H), 7.66-7.50 (m, 3H), 7.38(s, 1H), 4.21-4.09 (m, 1H), 3.89 (s, 3H), 3.82- 3.74 (s, 1H), 3.40-3.33(m, 2H), 3.23-3.10 (m, 1H), 2.85- 2.75 (m, 1H), 2.60-2.54 (m, 1H),2.40-2.30 (m, 1H), 2.28- 2.20 (m, 1H), 1.98-1.86 (m, 1H), 1.22-1.10 (m,4H), 0.95 (d, J = 6.6 Hz, 3H). II-12

4 575.2 DMSO-d₆: δ 7.96-7.95 (m, 1H), 7.65-7.63 (m, 2H), 7.56- 7.51 (m,1H), 7.38-7.37 (m, 1H), 4.14-4.13 (m, 1H), 3.88 (s, 3H), 3.75-3.72 (m,1H), 3.43-3.40 (m, 1H), 3.31-3.12 (m, 3H), 2.78-2.74 (m, 1H), 2.51-2.50(m, 1H), 2.27-2.19 (m, 1H), 1.91-1.83 (m, 1H), 1.36-1.34 (m, 6H), 0.91(d, J = 6.5 Hz, 3H). II-13

4 573.2 DMSO-d₆: δ 12.75 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.65 (d, J =8.0 Hz, 2H), 7.57-7.53 (m, 1H), 7.37 (d, J = 1.2 Hz, 1H), 4.31-4.12 (m,1H), 3.88 (s, 3H), 3.81-3.61 (m, 1H), 3.29-3.28 (m, 2H), 3.18-3.11 (m,1H), 2.82-2.80 (m, 1H), 2.59-2.50 (m, 1H), 2.36-2.34 (m, 1H), 2.25-2.23(m, 1H), 1.93-1.92 (m, 1H), 1.15-1.11 (m, 4H), 0.99-0.90 (m, 3H). II-14

4 574.3 DMSO-d₆: δ 12.62 (s, 1H), 7.98 (s, 1H), 7.69-7.67 (m, 3H),7.57-7.52 (m, 1H), 7.37 (s, 1H), 4.16 (s, 1H), 3.87 (s, 3H). 3.75-3.71(m, 1H), 3.35-3.32 (m, 2H), 3.24- 3.17 (m, 1H), 3.00-2.96 (m, 1H),2.76-2.73 (m, 1H), 2.44 (s, 1H), 2.26-2.22 (m, 1H), 1.93-1.87 (m, 1H),1.27-1.21 (m, 6H), 1.21-0.71 (m, 3H). II-15

4 574.2 DMSO-d₆: δ 7.96 (d, J = 1.6 Hz, 1H), 7.70-7.68 (m, 3H),7.58-7.54 (m, 1H), 7.38 (d, J = 1.6 Hz, 1H), 4.15 (s, 1H), 3.88 (s, 3H),3.74-3.69 (m, 1H), 3.39-3.32 (m, 2H), 3.24-3.17 (m, 1H), 3.02-2.95 (m,1H), 2.76-2.68 (m, 1H), 2.48-2.45 (m, 1H), 2.34-2.23 (m, 1H), 1.94-1.87(m, 1H), 1.28-1.22 (m, 6H), 0.92 (d, J = 6.8 Hz, 3H). II-16

4 589.3 DMSO-d₆: δ 12.8 (s, 1H), 8.01 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H),7.55-.51 (m, 1H), 7.39 (s, 1H), 3.91 (s, 3H), 3.41-3.35 (m, 1H), 3.22(s, 2H), 2.90 (s, 1H), 2.74 (s, 1H), 2.39 (s, 2H), 2.19 (s, 2H),1.36-1.33 (m, 12H). II-17

4 587.3 CD₃OD-d₄: δ 8.02-7.99 (m, 1H), 7.61-7.46 (m, 4H), 4.00 (s, 3H),3.40-3.33 (m, 3H), 2.52-2.10 (m, 4H), 3.24 (s, 2H), 1.41 (d, J = 6.9 Hz,6H), 1.15-1.00 (m, 2H), 0.75-0.65 (m, 2H). II-18

4 589.2 DMSO-d₆: δ 12.72 (s, 1H), 7.96 (s, 1H), 7.66-7.50 (m, 3H), 7.37(s, 1H), 3.88 (s, 3H), 3.86-3.75 (m, 2H), 3.41- 3.30 (m, 1H), 3.28-3.00(m, 3H), 2.77-2.62 (m, 2H), 2.16- 2.11 (m, 1H), 1.89-1.78 (m, 1H),1.42-1.30 (m, 8H), 0.62 (t, J = 7.5 Hz, 3H). II-19

4 603.2 DMSO-d₆: δ 12.75 (s, 1H), 7.96 (s, 1H), 7.69-7.50 (m, 3H), 7.36(s, 1H), 4.10-3.93 (m, 1H), 3.87 (s, 3H), 3.60- 3.33 (m, 2H), 3.30-3.03(m, 3H), 2.88-2.68 (m, 2H), 2.10- 2.00 (m, 1H), 1.92-1.75 (m, 2H), 1.33(t, J = 6.6 Hz, 6H), 0.70 (d, J = 6.9 Hz, 3H), 0.61 (d, J = 6.6 Hz, 3H).II-20

4 589.1 DMSO-d₆: δ 7.95 (d. J = 1.2 Hz, 1H), 7.65-7.63 (m, 2H),7.55-7.53 (m, 1H), 7.40 (s, 1H), 3.88 (s, 3H), 3.66-3.62 (m, 1H),3.51-3.34 (m, 4H), 3.15-3.07 (m, 1H), 2.72-2.68 (m, 1H), 2.27-2.26 (m,1H), 2.19-2.16 (m, 1H), 1.42-1.40 (m, 1H), 1.35-1.32 (m, 6H), 1.23-1.20(m, 1H), 0.66 (t, J = 7.2 Hz, 3H). II-21

4 587.3 DMSO-d₆: δ 7.97 (s, 1H), 7.64-7.62 (m, 2H), 7.57-7.53 (m, 1H),7.40 (s, 1H), 3.88 (s, 3H), 3.68-3.65 (m, 1H), 3.54- 3.50 (m, 3H),3.23-3.09 (m, 2H), 2.77-2.73 (m, 1H), 2.37- 2.22 (m, 3H), 1.47-1.43 (m,1H), 1.25-1.21 (m, 1H), 1.15- 1.08 (m, 4H), 0.65 (t, J = 7.6 Hz, 3H)II-23

6 587.2 DMSO-d₆: δ 12.70 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.64-7.62(m, 2H), 7.58-7.53 (m, 1H), 7.37 (d, J = 1.6 Hz, 1H), 3.88 (s, 3H), 3.48(s, 2H), 3.31 (d, J = 4.8 Hz, 2H), 3.02 (s, 2H), 2.50-2.47 (m, 2H),2.33-2.27 (m, 1H), 1.15- 1.11 (m, 4H), 0.75 (s, 6H). II-24

6 575.2 DMSO-d₆: δ 12.73 (s, 1H), 7.98 (d, J = 1.2 Hz, 1H), 7.64-7.62(m, 2H), 7.57-7.53 (m, 1H), 7.38 (d, J = 1.2 Hz, 1H), 3.88 (s, 3H),3.70- 3.55 (m, 3H), 3.38-3.33 (m, 1H), 3.21-3.16 (m, 1H), 3.00 (d, J =14 Hz, 1H), 2.71-2.66 (m, 2H), 2.40-2.34 (m, 1H), 2.13-2.10 (m, 1H),1.34- 1.31 (m, 6H), 0.75 (m, 3H). II-25

6 573.3 DMSO-d₆: δ 12.75 (s, 1H), 7.99 (s, 1H), 7.64-7.62 (m, 2H),7.57-7.53 (m, 1H), 7.38 (d, J = 0.8 Hz, 1H), 3.88 (s, 3H), 3.72-3.56 (m,3H), 3.21- 3.16 (m, 1H), 3.08 (d, J = 13.6 Hz, 1H), 2.73-2.68 (m, 2H),2.50 (s, 1H), 2.42-2.13 (m, 2H), 1.23-1.08 (m, 4H), 0.76 (d, J = 6.4 Hz,3H). II-26

6 575.2 DMSO-d₆: δ 12.75 (s, 1H), 7.99 (s, 1H), 7.65-7.54 (m, 3H),7.44-7.38 (m, 1H), 3.89 (s, 3H), 3.70-3.56 (m, 3H), 3.21-3.16 (m, 1H),2.30-2.27 (m, 1H), 2.71-2.60 (m, 2H), 2.38 (s, 2H), 2.21-2.11 (m, 1H),1.47-1.32 (m, 6H), 1.75 (s, 3H). II-27

4 573.0 CD₃OD-d₄: δ 7.95 (d, J = 1.2 Hz, 1H), 7.55-7.46 (m, 4H), 3.97(s, 3H), 3.84 (d, J = 14 Hz, 1H), 3.74-3.69 (m, 2H), 3.29-3.25 (m, 1H),3.11 (d, J = 14 Hz, 1H), 3.86-3.76 (m, 2H), 2.45-2.42 (m, 1H), 2.28-2.17 (m, 2H), 1.17 (d, J = 6.8 Hz, 4H), 0.85 (d, J = 6.4 Hz, 3H). II-28

4 575.1 DMSO-d₆: δ 7.96 (s, 1H), 7.65-7.64 (m, 2H), 7.57-7.55 (m, 1H),7.39 (m, 1H), 3.87 (s, 3H), 3.68 (m, 4H), 3.16 (s, 1H), 2.99-2.96 (m,1H), 2.68- 2.66 (m, 2H), 2.24 (m, 1H), 2.12 (m, 1H), 1.35-1.31 (m, 6H),0.75 (s, 3H). II-29

4 603.2 DMSO-d₆: δ 7.98 (s, 1H), 7.49 (s, 1H), 7.40-7.38 (m, 2H),7.33-7.30 (m, 1H), 3.92- 3.82 (m, 4H), 3.71-3.67 (m, 1H), 3.32-3.23 (m,2H), 3.09- 2.84 (m, 3H), 2.62 (s, 2H), 2.11 (s, 2H), 1.42-1.36 (m, 5H),0.90 (s, 3H), 0.52 (s, 3H). II-30

6 587.0 DMSO-d₆: δ 7.95-7.94 (m, 1H), 7.62-7.55 (m, 3H), 7.40- 7.38 (m,1H), 3.87 (s, 3H), 3.67 (s, 2H), 3.60-3.50 (m, 2H), 3.40-3.32 (m, 3H),2.79- 2.71 (m, 2H), 1.35 (d, J = 6.9 Hz, 6H), 0.47-0.45 (m, 2H),0.15-0.18 (m, 2H). II-31

4 591.3 CD₃OD-d₄: δ 8.03 (s, 1H), 7.61-7.59 (m, 3H), 7.58 (m, 1H),4.39-4.20 (m, 3H), 4.11- 4.09 (m, 4H), 3.33-3.32 (m, 1H), 3.12-3.09 (m,4H), 2.03 1.96 (m, 6H), 1.26-1.24 (m, 3H), 1.15 (s, 3H). II-32

4 589.2 DMSO-d₆: δ 7.93 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H),7.57-7.55 (m, 1H), 7.37 (d, J = 1.2 Hz, 1H), 4.15 (s, 1H), 3.87 (s, 3H),3.22-3.57 (m, 5H), 2.91-2.89 (m, 1H), 2.80-2.51 (m, 1H), 2.23-2.19 (m,1H), 1.37-1.34 (m, 6H), 0.98-0.89 (m, 3H), 0.85-0.75 (m, 3H). II-33

4 591.2 DMSO-d₆: δ 7.92 (d, J = 1.2 Hz, 1H), 7.88-7.62 (m, 2H),7.58-7.51 (m, 1H), 7.37 (s, 1H), 4.16 (s, 1H), 3.66 (s, 3H), 3.56-3.38(m, 3H), 3.28- 3.21 (m, 2H), 2.90-2.88 (m, 1H), 2.78-2.74 (m, 1H), 2.23-2.19 (m, 1H), 1.36-1.34 (m, 6H), 0.93 (m, 3H), 0.78 (m, 3H). II-34

6 587.2 CDCl₃: δ 8.00 (s, 1H), 7.61- 7.51 (m, 1H), 7.50-7.39 (m, 2H),7.33-6.91 (m, 1H), 4.29 (s, 1H), 4.01 (s, 3H), 3.65- 3.61 (m, 1H),3.54-3.49 (m, 2H), 3.31-3.26 (m, 1H), 3.04 2.90 (m, 1H), 2.89-2.85 (m,1H), 2.26-2.19 (m, 1H), 2.18 2.12 (m, 1H), 1.40-1.21 (m, 2H), 1.20-1.10(m, 2H), 1.09- 1.03 (m, 3H), 0.97-0.90 (m, 3H). II-35

6 587.1 DMSO-d₆: δ 7.95 (s, 1H), 7.67-7.64 (m, 2H), 7.59-7.55 (m, 1H),7.41-7.35 (m, 1H), 4.21-4.12 (m, 1H), 3.93-3.86 (m, 4H), 3.70-3.67 (m,1H), 2.86-2.73 (m, 2H), 2.71-2.62 (m, 1H), 2.42-2.32 (m, 1H), 2.25-2.16(m, 2H), 1.18-1.08 (m, 7H), 0.91-0.90 (d, J = 6.0 Hz, 3H) II-36

4 585.0 CDCl₃: δ 7.96 (s, 1H), 7.48- 7.41 (m, 1H), 7.39-7.31 (m, 2H),7.29-7.26 (m, 1H), 4.49- 4.31 (m, 2H), 3.89-3.24 (m, 3H), 3.24 (s, 2H),2.64-2.61 (m, 2H), 2.38-2.35 (m, 2H), 2.16-2.07 (m, 1H), 1.81-1.71 (m,2H), 1.70-1.68 (m, 2H), 1.23-1.22 (m, 2H), 1.16-1.07 (m, 2H). II-37

6 585.1 CDCl₃: δ 8.01 (s, 1H), 7.60- 7.51 (m, 1H), 7.40-7.38 (m, 2H),7.29-7.26 (m, 1H), 4.02 (s, 3H), 3.69-3.66 (m, 2H), 3.49-3.34 (m, 2H),3.25-3.15 (m, 4H), 2.28-2.19 (m, 1H), 1.86-1.75 (m, 2H), 1.67-1.53 (m,2H), 1.47-1.21 (m, 2H), 1.19-1.06 (m, 2H). II-38

4 599.2 DMSO-d₆: δ 12.73 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.65-7.63(m, 2H), 7.56-7.52 (m, 1H), 7.38 (d, J = 1.2 Hz, 1H), 3.89 (s, 3H),3.75-3.50 (m, 4H), 3.34-3.33 (m, 2H), 2.74-2.73 (m, 2H), 2.46- 2.42 (m,1H), 1.71-1.6 (m, 3H), 1.49-1.47 (m, 2H), 1.36- 1.35 (m, 1H), 1.15-1.10(m, 4H). II-39

4 615.2 DMSO-d₆: δ 8.01 (s, 1H), 7.56-7.51 (m, 1H), 7.40-7.32 (m, 3H),4.15-3.74 (m, 5H), 3.52-3.46 (m, 1H), 3.25-3.20 (m, 1H), 2.94-2.92 (m,1H), 2.68-2.64 (m, 1H), 2.38-2.30 (m, 1H), 2.12-2.07 (m, 1H), 1.90-1.85(m, 1H), 1.78-1.63 (m, 1H), 1.40-1.26 (m, 10H), 1.06-0.75 (m, 2H),0.45-0.36 (m, 1H). II-40

4 575.3 DMSO-d₆: δ 8.05 (s, 1H), 7.55 (s, 1H), 7.40-7.38 (m, 2H),7.32-7.30 (m, 1H), 4.05 (s, 3H), 3.68 (s, 3H), 3.37 (s, 2H), 3.32-3.25(m, 1H), 2.68- 2.66 (m, 2H), 2.53-2.50 (m, 2H), 1.83-1.80 (m, 2H), 1.48(s, 1H), 1.41-1.40 (d, J = 5.3 Hz, 6H). II-41

4 589.2 CDCl₃: δ 8.05-8.00 (m, 1H), 7.61-7.32 (m, 4H), 4.52-3.87 (m,6H), 3.64-3.17 (m, 3H), 2.89-2.50 (m, 2H), 2.34-1.95 (m, 2H), 1.45-1.17(m, 11H). II-42

4 587.2 CDCl₃: δ 8.05 (m, 1H), 7.61- 7.57 (m, 1H), 7.51-7.32 (m, 3H),4.06-3.87 (m, 6H), 3.64- 3.40 (m, 1H), 3.39-16 (m, 2H), 2.89-2.53 (m,3H), 2.50- 1.95 (m, 2H), 1.45-1.38 (m, 8H), 1.28-1.17 (m, 3H). II-43

7 560.1 CDCl₃: δ 8.01 (s, 1H), 7.61 (s, 1H), 7.46-7.34 (m, 3H),4.19-4.14 (m, 2H), 4.02 (s, 3H), 3.18-3.11 (m, 1H), 3.09- 2.96 (m, 2H),2.25 (d, J = 9.1 Hz, 2H), 1.66 (m, 2H), 1.39 (d, J = 6.2 Hz, 7H),1.25-1.13 (m, 2H). II-44

7 559.2 CD₃OD-d₄: δ 7.95 (d, J = 1.2 Hz, 1H), 7.68-7.50 (m, 5H), 4.13(d, J = 13.2 Hz, 2H), 3.97 (s, 3H), 3.03-2.86 (m, 3H), 2.51 (d, J = 7.6Hz, 2H), 1.68-1.54 (m, 3H), 1.30-1.22 (m, 8H). II-48

8 546.3 DMSO-d₆: δ 13.13 (s, 1H), 8.21 (s, 1H), 7.62-7.49 (m, 4H), 3.98(s, 3H), 3.75 (s, 1H), 3.44-3.40 (m, 2H), 2.73 (s, 3H), 2.29 (s, 2H),1.98 (s, 1H), 1.33-1.29 (m, 7H). II-49

7 559.2 CD₃OD-d₄: δ 8.75 (s, 2H), 8.02 (d, J = 1.2 Hz, 1H), 7.61 (d, J =1.2 Hz, 1H), 4.18-4.15 (d, J = 12.0 Hz, 2H), 4.03 (s, 3H), 3.33-3.32 (m,2H), 2.44- 2.42 (d, J = 8.0 Hz, 2H), 2.26-2.20 (m, 1H), 1.82-1.79 (d, J= 12.0 Hz, 2H), 1.63- 1.58 (m, 1H), 1.39-1.28 (m, 2H), 1.29-1.26 (d, J =12.0 Hz, 4H). II-50

7 574.2 CD₃OD-d₄: δ 7.98 (s, 1H), 7.68-7.64 (m, 1H), 7.58-7.51 (m, 4H),4.12-4.08 (d, J = 12.0 Hz, 2H), 4.00 (s, 3H), 3.08-3.03 (m, 2H),2.50-2.49 (d, J = 4.0 Hz, 2H), 2.20-2.16 (m, 1H), 1.69-1.66 (d, J = 12.0Hz, 2H), 1.58-1.54 (m, 1H), 1.28-1.14 (m, 6H). II-51

7 572.1 DMSO-d₆: δ 12.7 (s, 1H), 7.97 (s, 1H), 7.71-7.58 (m, 3H), 7.37(s, 1H), 4.38 (s, 1H), 3.88 (s, 3H), 3.07-3.26 (m, 1H), 2.14-2.35 (m,3H), 1.68-1.40 (m, 5H), 1.21-1.00 (m, 8H). *It is to be understood thatring A attaches to the thiazole ring at the open valence on theleft-hand side of ring A and to the B-ring at the open valence on theright-hand side of ring A.

TABLE 3

LC-MS Compound A* B X Scheme (M + H)⁺ ¹HNMR (ppm) III-01

S 4 531.2 DMSO-d₆: δ 12.62 (s, 1H), 8.36 (s, 1H), 7.86 (d, J = 8.1 Hz,1H), 7.65-7.53 (m, 3H), 7.46 (d, J = 8.4 Hz, 1H), 3.41 (s, 4H), 3.34 (s,2H), 3.27 (s, 1H), 2.35 (s, 4H), 1.35 (d, J = 6.9 Hz, 6H). III-02

S 4 531.3 CD₃OD-d₄: δ 8.32 (s, 1H), 7.98-7.95 (m, 1H), 7.58-7.50 (m,4H), 3.56-3.48 (m, 4H), 3.42 (s, 2H), 2.50-2.46 (m, 4H), 2.34-2.28 (m,1H), 1.20- 1.17 (m, 4H). III-03

S 6 543.1 CDCl₃: δ 8.30 (s, 1H), 8.12- 7.92 (m, 1H), 7.60-7.46 (m, 1H),7.41-7.39 (m, 2H), 7.33- 7.28 (m, 1H), 4.18 (s, 1H), 3.97-3.71 (m, 1H),3.48-3.22 (m, 3H), 2.98-2.81 (m, 1H), 2.69-2.53 (m, 1H), 2.25- 2.16 (m,1H), 2.21-2.12 (m, 1H), 2.01-1.92 (m, 1H), 1.30- 1.21 (m, 2H), 1.18-1.02(m, 5H). III-04

S 6 543.1 CDCl₃: δ 8.33 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.51-7.41 (m,1H), 7.39-7.34 (m, 2H), 7.31-7.26 (m, 1H), 3.82-3.78 (m, 1H), 3.71-3.67(m, 2H), 3.35-329 (m, 1H), 2.99 (m, 1H), 2.86-2.79 (m, 2H), 2.46- 2.42(m, 1H), 2.20-2.05 (m, 2H), 1.18-1.10 (m, 4H), 0.86 (d, J = 6.3 Hz, 3H).III-05

S 6 543.1 DMSO-d₆: δ 8.31 (s, 1H), 7.82 (d, J = 9.9 Hz, 1H), 7.64-7.57(m, 2H), 7.55-7.54 (m, 1H), 7.40 (d, J = 8.5 Hz, 1H), 3.72-3.67 (m, 3H),3.32- 3.15 (m, 1H), 3.06 (m, 1H), 2.72-2.70 (m, 2H), 2.62-2.35 (m, 2H),2.22-2.01 (m, 1H), 1.22-0.95 (m, 4H), 0.75 (d, J = 6 Hz, 3H). III-06

S 6 543.1 CDCl₃: δ 8.33 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.51-7.41 (m, 1H), 7.39-7.34 (m, 2H), 7.31-7.26 (m, 1H), 3.82-3.78 (m, 1H),3.71-3.67 (m, 2H), 3.35-3.29 (m, 1H), 3.02-2.97 (m, 1H), 2.86-2.79 (m,2H), 2.46-2.42 (m, 1H), 2.20-2.05 (m, 2H), 1.31-1.29 (m, 2H), 1.16-1.03(m, 2H), 0.86 (d, J = 6.3 Hz, 3H). III-07

S 6 557.1 CDCl₃: δ 8.30 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.48 (d, J =8.4 Hz, 1H), 7.43-7.31 (m, 2H), 7.30-7.26 (m, 1H), 4.30- 4.15(m, 1H),3.63-3.48 (m, 3H), 3.47-3.28 (m, 1H), 3.06- 3.05 (m, 1H), 2.90-2.85 (m,1H), 2.24-2.20 (m, 1H), 2.19- 2.13 (m, 1H), 1.30-1.26 (m, 2H), 1.16-1.05(m, 5H), 0.92 (d, J = 6.6 Hz, 3H). III-08

S 7 530.1 CDCl₃: δ 8.33 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.54-7.52 (m,1H), 7.46-7.43 (m, 2H), 7.38-7.33 (m, 1H), 4.16-4.12 (m, 2H), 3.18-2.98(m, 3H), 2.27 (d, J = 7.2 Hz, 2H), 1.75-1.71 (m, 2H), 1.40-1.31 (m, 7H),1.25-1.19 (m, 2H). III-09

S 4 515.3 CDCl₃: δ 8.00-7.94 (m, 2H), 7.40-7.32 (m, 4H), 3.55 (brs, 4H),3.29 (brs, 3H), 2.42 (brs, 4H), 1.43 (d, J = 6.9 Hz, 6H). *It is to beunderstood that ring A attaches to the thiazole/oxazole ring at the openvalence on the left-hand side of ring A and to the B-ring at the openvalence on the right-hand side of ring A.

TABLE 3I

LC-MS Compound A* B Scheme (M + H)⁺ ¹HNMR (ppm) III2-01

6 527.3 DMSO-d₆: δ 12.30 (s, 1H), 8.03 (s, 1H), 7.67-7.54 (m, 4H), 7.34(d, J = 8.7 Hz, 1H), 5.91 (s, 1H), 3.55 (s, 3H), 3.43-3.29 (m, 3H), 2.80(brs, 4H), 2.42 (brs, 4H), 1.35 (d, J = 6.9 Hz, 6H). *It is to beunderstood that ring A attaches to the pyrrole ring at the open valenceon the left-hand side of ring A and to the B-ring at the open valence onthe right-hand side of ring A.

TABLE 3II

LC-MS Compound A* B Scheme (M + H)⁺ ¹HNMR (ppm) III3-01

4 526.3 DMSO-d₆: δ 7.94-7.87 (m, 1H), 7.75-7.53 (m, 4H), 7.40-7.33 (m,1H), 3.58 (s, 3H), 3.34 (s, 2H), 3.17-3.08 (m, 4H), 2.43- 2.23 (m, 5H),1.15-1.06 (m, 4H). *It is to be understood that ring A attaches to theimidazole ring at the open valence on the left-hand side of ring A andto the B-ring at the open valence on the right-hand side of ring A.

TABLE 4

LC-MS Compound A* B Scheme (M + H)⁺ ¹HNMR (ppm) IV-01

4 545.3 DMSO-d₆: δ 12.60 (s, 1H), 8.17 (s, 1H), 7.69-7.62 (m, 3H),7.58-7.52 (m, 1H), 3.34-3.39 (m, 4H), 3.27 (s, 2H), 2.45 (s, 3H), 2.36(s, 4H), 1.34 (d, J = 6.9 Hz, 6H). IV-02

4 543.1 DMSO-d₆: δ 12.60 (brs, 1H), 8.17-8.16 (m, 1H), 7.69 (s, 1H),7.65-7.62 (m, 2H), 7.57-7.53 (m, 1H), 3.43-3.41 (m, 4H), 3.41-3.40 (m,2H), 2.49 (s, 3H), 2.45-2.33 (m, 5H), 1.16-1.11 (m, 4H). IV-03

4 544.4 DMSO-d₆: δ 8.18 (s, 1H), 7.69- 7.67 (m, 4H), 7.59-7.54 (m, 1H),3.42-3.39 (m, 6H), 3.01- 2.95 (m, 1H), 2.45 (s, 3H), 2.34 (brs, 4H),1.25-1.23 (m, 6H). IV-04

6 557.1 DMSO-d₆: δ 12.59 (s, 1H), 8.16 (s, 1H), 7.68-7.62 (m, 3H),7.56-7.49 (m, 1H), 4.14-4.06 (m, 1H), 3.83 (s, 1H), 3.32 (s, 1H),3.23-3.13 (m, 2H), 2.82- 2.78 (m, 1H), 2.59-2.56 (m, 1H), 2.44 (s, 3H),2.38-2.30 (m, 1H), 2.26-2.21 (m, 1H), 1.97- 1.88 (m, 1H), 1.17-1.08 (m,4H), 0.97-0.95 (d, J = 6.6 Hz, 3H). IV-05

6 557.3 DMSO-d₆: δ 12.52 (s, 1H), 8.19 (s, 1H), 7.79-7.63 (m, 3H),7.57-7.51 (m, 1H), 4.08-4.02 (m, 1H), 3.85-3.81 (m, 1H), 3.28-3.15 (m,3H), 2.90-2.73 (m, 1H), 2.60-2.50 (m, 1H), 2.45-2.37 (m, 4H), 2.27-2.15(m, 1H), 2.08-1.89 (m, 1H), 1.15-1.03 (m, 4H), 0.96 (d, J = 6.6 Hz, 3H).IV-06

6 559.1 DMSO-d₆: δ 12.59 (s, 1H), 8.16 (s, 1H), 7.68-7.51 (m, 4H),3.71-3.57 (m, 3H), 3.24-3.17 (m, 1H), 3.09-3.04 (m, 1H), 2.74-2.68 (m,2H), 2.44 (s, 3H), 2.32-2.28 (m, 2H), 2.19-2.12 (m, 1H), 1.13-1.06(m,4H), 0.76-0.74 (d, J = 6.1 Hz, 3H). IV-07

6 557.3 DMSO-d₆: δ 12.59 (brs, 1H), 8.16 (s, 1H), 7.68 (s, 1H), 7.64-7.61 (m, 2H), 7.57-7.52 (m, 1H), 3.82-3.57 (m, 3H), 3.24- 3.16 (m, 1H),3.09-3.04 (m, 1H), 2.75-2.65 (m, 2H), 2.44- 2.35 (m, 4H), 2.33-2.26 (m,1H), 2 2.-2.11 (m, 1H), 1.16- 1.04 (m, 4H), 0.76-0.74 (d, J = 6.0 Hz,3H). IV-08

6 570.8 DMSO-d₆: δ 12.57 (s, 1H), 8 13 (s, 1H), 7.67-7.63 (m, 3H),7.56-7.50 (m, 1H), 4.18 (s, 1H), 3.62-3.51 (m, 2H), 3.39-3.37 (m, 1H),3.27-3.22 (m, 1H), 2.96-2.93 (m, 1H), 2.82-2.72 (m, 1H), 2.43 (s, 3H),2.40-2.33 (m, 1H), 2.27-2.21 (m, 1H), 1.17-1.06 (m, 4H), 0.97-0.94 (d, J= 6.6 Hz, 3H), 0.86-0.84 (d, J = 6.5 Hz, 3H). IV-09

6 571.1 DMSO-d₆: δ 8.15(s, 1H), 7.68- 7.56 (m, 4H), 4.17 (s, 1H),3.89-3.84 (m, 1H), 3.74-3.67 (m, 1H), 2.88-2.68 (m, 3H), 2.44 (s, 3H),2.40-2.18 (m, 3H), 1.12-1.10 (m, 7H), 0.90-0.88 (d, J = 5.9 Hz, 3H).IV-10

7 544.1 DMSO-d₆: δ 8.15 (s, 1H), 7.69- 7.67 (m, 3H), 7.61-7.57 (m, 1H),4.03-4.00 (m, 2H), 3.33- 3.25 (m, 1H), 3.01-2.96 (m, 2H), 2.44 (s, 3H),2.33-2.25 (m, 2H), 1.62-1.59 (m, 2H), 1.36- 1.32 (m, 1H), 1.32-1.30 (d,J = 6.8 Hz, 6H), 1.23-1.16 (m, 2H). *It is to be understood that ring Aattaches to the thiazole ring at the open valence on the left-hand sideof ring A and to the B-ring at the open valence on the right-hand sideof ring A.

TABLE 5

LC-MS Compound R¹ A* B Scheme (M + H)⁺ ¹HNMR (ppm) V-01 Me

6 557.2 DMSO-d₆: δ 8.20 (s, 1H), 7.79-7.76 (m, 2H), 7.64- 7.62 (m, 1H),7.25-7.22 (m, 1 H), 4.16 (s, 1H), 3.76-3.71 (m, 1H), 3.28-3.20 (m, 4H),2.81-2.77 (m, 1H), 2.54- 2.50 (m, 4H), 2.37-2.36 (m, 1H), 1.95-1.92 (m,1H), 1.13-1.06 (m, 4H), 0.96- 0.94 (m, 3H). V-02 F

6 561.2 DMSO-d₆: δ 13.10 (s, 1H), 8.24 (m, 1H), 7.64 (m, 2H), 7.53-7.50(m, 1H), 7.23- 7.19 (m, 1H), 4.15 (s, 1H), 3.75 (m, 1H), 3.19-3.15 (m,3H), 2.80-2.77 (m, 1H), 2.50-2.49 (m, 1H), 2.34- 2.32 (m, 1H), 2.24-2.21(m. 1H), 1.95-1.92 (m, 1H), 1.16-1.11 (m, 4H), 0.96- 0.93 (m, 3H). *Itis to be understood that ring A attaches to the thiazole ring at theopen valence on the left-hand side of ring A and to the B-ring at theopen valence on the right-hand side of ring A.

TABLE 6

LC-MS Compound A* B Scheme (M + H)⁺ ¹HNMR (ppm) VI-01

4 549.1 CDCl₃: δ 8.09 (s, 1H), 5 7.73 (d, J = 10.2 Hz, 1H), 7.41-7.39(m, 2H), 7.34-7.26 (m, 1H), 3.50-3.47 (m, 4H), 3.33-3.23 (m, 3H),2.39-2.43 (m, 4H), 1.42-1.38 (m, 6H). VI-02

4 546.7 DMSO-d₆: δ 12.94 (brs, 1H), 8.23-8.22 (m, 1H), 7.65-7.52 (m,4H), 3.45-3.43 (m, 4H), 3.32-3.30 (m, 2H), 2.39-2.34 (m, 5H), 1.15-1.09(m, 4H). VI-03

4 548.0 DMSO-d₆: δ 8.18 (s, 1H), 7.69- 7.67 (m, 3H), 7.59-7.54 (m, 2H),3.41 (s, 6H), 3.01-2.94 (m, 1H), 2.34 (s, 4H), 1.25 (d, J = 6.8 Hz, 6H).VI-04

6 561.0 DMSO-d₆: δ 8.15 (s, 1H), 7.63 (d, J = 8 Hz, 2H), 7.57-7.52 (m,2H), 4.16 (s, 1H), 3.77 (d, J = 10.8 Hz, 1H), 3.31-3.24 (m, 2H),3.23-3.16 (m, 1H), 2.82 (d, J = 11.6 Hz, 1H), 2.67-2.56 (m, 1H),2.39-2.32 (m, 1H), 2.26-2.22 (m, 1H), 1.96-1.90 (m, 1H), 1.17-1.11 (m,4H), 1.10-0.95 (m, 3H). VI-05

6 561.3 CD₃OD-d₄: δ 8.19 (s, 1H), 7.70-7.55 (m, 4H), 4.69-4.50 (m, 1H),4.28-4.02 (m, 3H), 3.79-3.35 (m, 3H), 3.24-2.85 (m, 2H), 2.60-2.40 (m,1H), 1.38-1.30 (m, 7H). VI-06

6 561.1 DMSO-d₆: δ 8.17 (d, J = 1.2 Hz, 1H), 7.65-7.54 (m, 4H),3.72-3.60 (m, 3H), 3.26-3.20 (m, 1H), 3.09 (d, J = 13.6 Hz, 1H),2.76-2.71 (m, 2H), 2.44- 2.40 (m, 1H), 2.34-2.30 (m, 1H), 2.20-2.14 (m,1H), 1.15- 1.09 (m, 4H), 0.75 (d, J = 6.4 Hz, 3H). VI-07

6 561.1 DMSO-d₆: δ 8.12 (s, 1H), 7.65- 7.56 (m, 2H), 7.55-7.53 (m, 2H),3.72-3.59 (m, 3H), 3.28- 3.17 (m, 1H), 3.09 (d, J = 13.6 Hz, 1H),2.75-2.70 (m, 2H), 2.42-2.41 (m, 1H), 2.33- 2.29 (m, 1H), 2.19-2.10 (m,1H), 1.14-1.07 (m, 4H), 0.76 (d, J = 6.0 Hz, 3H). VI-08

6 575.3 DMSO-d₆: δ 8.13 (s, 1H), 7.65 (d, J = 8 Hz, 2H), 7.56-7.52 (m,2H), 4.16 (s, 1H), 3.60-3.53 (m, 2H), 3.39-3.35 (m, 1H), 3.32- 3.23 (m,1H), 2.96 (d, J = 2.8 Hz, 1H), 2.83-2.78 (m, 1H), 2.40-2.33 (m, 1H),2.24 (d, J = 10.8 Hz, 1H), 1.15-1.08 (m, 4H), 0.96 (d, J = 6.8 Hz, 3H),0.86 (d, J = 6.4 Hz, 3H). VI-09

6 575.1 DMSO-d₆: δ 8.13 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.57-7.52 (m,2H), 4.17 (s, 1H), 3.61-3.53 (m, 2H), 3.39-3.35 (m, 1H), 3.32-3.23 (m,1H), 2.96 (s, 1H), 2.83-2.79 (m, 1H), 2.40-2.33 (m, 1H), 2.24 (d, J =11.6 Hz, 1H), 1.16-1.08 (m, 4H), 0.96 (d, J = 6.8 Hz, 3H), 0.86 (d, J =6.4 Hz, 3H). VI-10

6 575.3 CD₃OD-d₄: δ 8.21 (s, 1H), 7.70-7.60 (m, 1H), 7.57-7.53 (m, 3H),4.69-4.34 (m, 2H), 4.20-3.91 (m, 2H), 3.64-3.31 (m, 2H), 3.22-2.81 (m,2H), 2.51-2.44 (m, 1H), 1.59-1.44 (m, 3H), 1.33-1.12 (m, 7H). VI-11

7 548.1 DMSO-d₆: δ 8.15 (s, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.62-7.57 (m,2H), 4.02 (d, J = 12.4 Hz, 2H), 3.05-2.95 (m, 2H), 2.33- 2.25 (m, 2H),1.63 (d, J = 11.6 Hz, 2H), 1.38-1.31 (m, 7H), 1.24-1.20 (m, 3H). *It isto be understood that ring A attaches to the thiazole ring at the openvalence on the left-hand side of ring A and to the B-ring at the openvalence on the right-hand side of ring A.

TABLE 7

LC-MS Compound R² A* B Scheme (M + H)⁺ ¹HNMR (ppm) VII-02 Cl

6 579.1 DMSO-d₆: δ 8.23 (s, 1H), 7 81 (s, 1H), 7.65-7.62 (m, 2H),7.56-7.51 (m, 1H), 4.16 (s, 1H), 4.36-4.34 (m, 1H), 3.84-3.79 (m, 1H),3.20-3.16 (m, 2H), 2.82-2.56 (m, 3H), 2.37-2.23 (m, 1H), 1.93-1.90 (m,1H), 1.15-1.12 (m, 4H), 0.98-0.95 (d, J = 6.6 Hz, 3H). VII-03 CF3

9 611.0 DMSO-d₆: δ 8.46 (s, 1H), 8.32 (s, 1H), 7.45-7.36 (m, 2H),7.34-7.31 (m, 1H), 4.41-3.88 (brs, 2H), 3.48-3.21 (m, 3H), 2.96-2.90 (m,1H), 2.69-2.61 (m, 1H), 2.38-2.31 (m, 1H), 2.19-2.11 (m, 1H), 2.06-1.97(m, 1H), 1.32-1.26 (m, 2H), 1.18-1.01 (m, 5H). VII-05 Cl

4 593.1 DMSO-d₆: δ 12.98 (s, 1H), 8.32 (s, 1H), 7.82-7.51 (m, 5H), 4.18(s, 1H), 3.83 (s, 1H), 3.49-3.36 (m, 2H), 3.17-3.12 (m, 1H), 2.79 (d, J= 10.4 Hz, 1H), 2.64 (d, J = 11.2 Hz, 1H), 2.40- 2.31 (m, 1H), 2.23-2.16 (m, 1H), 2.01- 1.96 (m, 1H), 1.22- 0.85 (m, 7H). *It is to beunderstood that ring A attaches to the thiazole ring at the open valenceon the left-hand side of ring A and to the B-ring at the open valence onthe right-hand side of ring A.

Experimental details for Compound VIII-04 (Scheme 12)

tert-Butyl(2S)-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methyl]-2-methylpiperazine-1-carboxylate(Compound 12a): To a solution of tert-butyl(2S)-2-methylpiperazine-1-carboxylate (400 mg, 2.00 mmol) indichloromethane (6 mL) was added acetic acid (120 mg, 2.0 mmol) and5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbaldehyde (562 mg,1.99 mmol). After the mixture was stirred for 30 min, NaBH(OAc)₃ (1.3 g,6.13 mmol) was added. The resulting solution was stirred overnight atroom temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (30:70). This resulted in 670mg (72%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=466.2.

(S)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((3-methylpiperazin-1-yl)methyl) isoxazole (Compound 12b): To a solution of Compound 12a (620 mg,1.3 mmol) in dioxane (4 mL) was added a solution of HCl in dioxane (8mL, 4M). The resulting solution was stirred for 2 h at room temperature.The resulting mixture was concentrated under vacuum. This resulted in 48mg (98%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=366.2.

(S)-Methyl 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl) isoxazol-4-yl)methyl)-2-methylpiperazin-1-yl)-7-methoxybenzo[d]thiazole-5-carboxylate(Compound 12c): To a solution of Compound 12b (100 mg, 0.27 mmol) inDMSO was added potassium carbonate (162 mg, 1.16 mmol) and methyl2-chloro-7-methoxy-1,3-benzothiazole-5-carboxylate (143 mg, 0.55 mmol).The resulting solution was stirred for 2 h at 120° C. The reaction wasthen quenched by the addition of 5 mL of water. The resulting solutionwas diluted with 50 mL of ethyl acetate. The resulted mixture was washedwith water and brine. The residue was concentrated under vacuum afterdried over anhydrous sodium sulfate. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (24:76). Thisresulted in 120 mg (75%) of the title compound as a light yellow solid.LC-MS (ESI, m/z): [M+H]⁺=587.2.

(S)-2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl) isoxazol-4-yl)methyl)-2-methylpiperazin-1-yl)-7-methoxybenzo[d]thiazole-5-carboxylicacid (Compound 12d): To a solution of Compound 12c (100 mg, 0.17 mmol)in a mixed solvent of tetrahydrofuran/methanol/H₂O (5 mL, 1:1:1) wasadded sodium hydroxide (30 mg, 0.75 mmol). The resulting solution wasstirred for 3 h at 50° C. The pH value of the solution was adjusted to 6with hydrogen chloride (2 N). The resulting solution was extracted withdichloromethane 3 times and the organic layers were combined. Theorganic phase was washed successively with water and brine. The residuewas concentrated under vacuum after dried over anhydrous sodium sulfate.The residue was applied onto a silica gel column withdichloromethane/methanol (15:1). This resulted in 60 mg (61%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=573.2.

(S)-2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl) isoxazol-4-yl)methyl)-2-methylpiperazin-1-yl)-7-methoxybenzo[d]thiazole-5-carboxamide(Compound VIII-04): To a solution of Compound 12d (60 mg, 0.1 mmol) inDMF (2 mL) was added CDI (18 mg, 0.11 mmol) at room temperature. NH₃.H₂O(0.1 ml, 25%, w %) was added into the mixture solution after stirred for1 h. The resulting solution was stirred for another 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a reverse column with H₂O/CH₃CN (60:40). Thisresulted in 6.4 mg (13%) of the title compound as a white solid. LC-MS(ESI, m/z): [M+H]⁺=572.1. ¹HNMR (300 MHz, DMSO-d₆, ppm): δ 7.91 (s, 1H),7.70-7.58 (s, 3H), 7.40 (s, 1H), 4.44 (s, 1H), 4.02-3.97 (m, 3H), 3.88(s, 3H), 3.25 (s, 1H), 3.11 (s, 1H), 2.98-2.81 (m, 2H), 2.72-2.66 (m,2H), 1.30-1.15 (m, 7H).

Experimental details for Compound VIII-03 (Scheme 13)

Methyl2-[(2R)-4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methyl]-2-methylpiperazin-1-yl]-4-methoxy-1,3-benzothiazole-6-carboxylate(Compound 13a): To a solution of methyl4-methoxy-2-[(2R)-2-methylpiperazin-1-yl]-1,3-benzothiazole-6-carboxylate(110 mg, 0.34 mmol) and5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazole-4-carbaldehyde(116 mg, 0.41 mmol) in dichloromethane (6 mL) was added NaOAc (93 mg,0.68 mmol). The mixture was stirred for 1 h at room temperature thenNaBH(OAc)₃ (291 mg, 1.37 mmol) was added. The resulting mixture wasstirred overnight at room temperature. The mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:4). This resulted in 150 mg (74%) ofthe title compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=588.1.

2-[(2R)-4-[[5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methyl]-2-methylpiperazin-1-yl]-4-methoxy-1,3-benzothiazole-6-carboxylicacid (Compound 13b): To a solution of Compound 13a (150 mg, 0.25 mmol)in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL) wasadded a solution of sodium hydroxide (51 mg, 1.28 mmol) in water (2 mL).The resulting solution was stirred for 2 h at 50° C. The pH value of themixture was adjusted to 5 with hydrogen chloride (2 N). The mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (15:1). This resulted in 90 mg(61%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=574.1.

2-[(2R)-4-[[5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methyl]-2-methylpiperazin-1-yl]-4-methoxy-1,3-benzothiazole-6-carboxamide(Compound VIII-03): To a solution of Compound 13b (90 mg, 0.16 mmol,) inDMF (3 mL) was added CDI (25 mg, 0.15 mmol). Ammonia water (0.2 mL) wasadded one portion after the mixture was stirred for 30 min. Theresulting mixture was stirred for 2 h at room temperature. The reactionsolution was concentrated under vacuum. The residue was applied onto aC18 column with ACN/H₂O (1:1). This resulted in 48.8 mg (54%) of thetitle compound as a white solid. LC-MS (ESI, m/z): [M+H]⁺=573.2. ¹HNMR(400 MHz, CD₃OD-d₄, ppm): δ 8.70 (d, J=0.8 Hz, 2H), 7.83 (d, J=1.6 Hz,1H), 7.43 (d, J=1.6 Hz, 1H), 4.20-4.17 (m, 1H), 3.99 (s, 3H), 3.85 (d,J=12.4 Hz, 1H), 3.43-3.20 (m, 3H), 2.86 (d, J=11.2 Hz, 1H), 2.61 (d,J=11.2 Hz, 1H), 2.36-2.25 (m, 2H), 2.05-2.01 (m, 1H), 1.19-1.05 (m, 4H),0.94-0.92 (d, J=6.5 Hz, 3H).

Following the procedure described above for Scheme 12 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

TABLE 8

LC-MS Compound A* B (M + H)⁺ ¹HNMR (ppm) VIII-01

560.3 CDCl₃: δ 7.67 (d, J = 1.5 Hz, 1H), 7.43-7.41 (m, 2H), 7.36-7.31(m, 2H), 4.03 (s, 3H), 3.50 (brs, 4H), 3.30 (brs, 2H), 2.43 (brs, 4H),1.44 (d, J = 6.9 Hz, 6H). VIII-02

572.1 DMSO-d₆: δ 7.88 (s, 2H), 7.65-7.62 (m, 2H), 7.58-7.51 (m, 1H),7.38 (s, 1H), 7.27 (s, 1H), 4.13 (s, 1H), 3.87 (s, 3H), 3.75-3.71 (m,1H), 3.28 (s, 1H), 3.23-3.11 (m, 2H), 2.81-2.72 (m, 1H), 2.58-2.57 (m,1H), 2.39- 2.20 (m, 1H), 1.95-1.86 (m, 1H), 1.17-1.07 (m, 4H), 0.94-0.92(d, J = 6.5 Hz, 3H). VIII-05

572.3 DMSO-d₆: δ 7.89 (s, 2H), 7.64-7.51 (m, 3H), 7.38 (s, 1H), 7.26 (s,1H), 3.87 (s, 3H), 3.72-3.54 (m, 3H), 3.18-3.03 (m, 2H), 2.73-2.69 (m,2H), 2.41-2.26 (m, 2H), 2.17-2.07 (m, 1H), 1.16-1.04 (m, 4H), 0.75- 0.73(d, J = 6 Hz, 3H). VIII-06

572.2 DMSO-d₆: δ 7.88 (s, 2H), 7.64-7.61 (m, 2H), 7.57-7.51 (m, 1H),7.38 (s, 1H), 7.26 (s, 1H), 3.87 (s, 3H), 3.72- 3.54 (s, 3H), 3.18-3.15(m, 1H), 3.11-3.03 (m, 1H), 2.74-2.63 (m, 2H), 2.41-2.36 (m, 1H),2.33-2.31 (m, 1H), 2.18-2.10 (m, 1H), 1.17- 1.04 (m, 4H), 0.76-0.74 (d,J = 6 Hz, 3H). VIII-07

586.2 DMSO-d₆: δ 7.86 (s, 2H), 7.65-7.63 (m, 2H), 7.56-7.51 (m, 1H),7.37 (s, 1H), 7.25 (s, 1H), 4.15-4.13 (s, 1H), 3.87 (s, 3H), 3.57-3.52(m, 2H), 3.27-3.22 (m, 1H), 2.97-2.93 (m, 1H), 2.84-2.72 (m, 1H),2.42-2.33 (m, 1H), 2.27-2.19 (m, 1H), 1.15- 1.06 (m, 4H), 0.93 (d, J =6.9 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H). *The A-ring is to be understoodas attaching to the thiazole ring at the open valence on the left-handside and to the B-ring at the open valence on the right-hand side.

Experimental details for Compound IX-01 and IX-02 (Scheme 14)

2-(4-((3-(2,6-Dichlorophenyl)-5-isopropylisoxazol-4-yl) methyl)piperazin-1-yl)-4-methoxybenzo[d]thiazole-6-carbonitrile (CompoundIX-01): To a solution of Compound VIII-01 (700 mg, 1.25 mmol) indichloromethane (5 mL) was added TEA (252 mg, 2.50 mmol). After coolingto 0° C., TFAA (529 mg, 5.45 mmol) in DCM (2 mL) was added in dropwise.The resulting solution was stirred for 15 min at 0° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with dichloromethane/methanol (94:6). This resulted in500 mg (74%) of the title compound as a white solid. LC-MS (ESI, m/z):[M+H]⁺=542.3. H-NMR (300 MHz, DMSO-d₆, ppm): δ 7.92 (s, 1H), 7.64-7.62(m, 2H), 7.57-7.52 (m, 1H), 7.27 (s, 1H), 3.88 (s, 3H), 3.39 (brs, 4H),3.34-3.26 (m 3H), 2.34 (brs, 4H), 1.34 (d, J=6.9 Hz, 6H).

3-(2,6-Dichlorophenyl)-5-isopropyl-4-((4-(4-methoxy-6-(1H-tetrazol-5-yl)benzo[d]thiazol-2-yl) piperazin-1-yl) methyl) isoxazole (CompoundIX-02): To a solution of Compound IX-01 (100 mg, 0.18 mmol) in toluene(3 mL) was added azidotrimethylsilane (42.5 mg, 0.37 mmol) andtetrabutylammonium fluoride (94 mg, 0.36 mmol). The resulting solutionwas stirred for 18 h at 85° C. The reaction was quenched by the additionof 10 mL of water. The resulting mixture was extracted with 3*20 mL ofethyl acetate and the organic layers were combined. The resulted mixturewas washed with water and brine. The residue was concentrated undervacuum after dried over anhydrous sodium sulfate. The crude product waspurified by a reverse chromatography with H₂O/CH₃CN (39:61). Thisresulted in 2.8 mg (3%) of the title compound as a white solid. LC-MS(ESI, m/z): [M+H]⁺=585.2. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.01 (s,1H), 7.64-7.63 (m, 2H), 7.57-7.52 (m, 2H), 3.95 (s, 3H), 3.45-3.37 (m,5H), 3.27 (s, 2H), 2.35 (brs, 4H), 1.34 (d, J=6.9 Hz, 6H).

Experimental details for Compound X-01 (Scheme 15)

tert-Butyl 4-(5-bromo-1-benzothiophen-2-yl) piperazine-1-carboxylate(Compound 15a): To a solution of 5-bromo-2-iodo-1-benzothiophene (500mg, 1.47 mmol) and tent-butyl piperazine-1-carboxylate (412 mg, 2.21mmol) in dioxane (5 mL) was added Pd₂(dba)₃.CHCl₃ (77 mg, 0.074 mmol),Xantphos (85 mg, 0.15 mmol) and Cs₂CO₃ (1.2 g, 3.68 mmol). The resultingsolution was stirred overnight at 60° C. The solids were filtered out.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:10). This resulted in 200 mg (34%) of the title compound as a yellowsolid. LCMS (ESI, m/z): [M+H]⁺=397.1.

1-(5-Bromo-1-benzothiophen-2-yl) piperazine (Compound 15b): To asolution of Compound 15a (200 mg, 0.50 mmol) in dioxane (3 mL) was addeda solution of hydrogen chloride in dioxane (6 mL, 4 M). The resultingsolution was stirred for 1 h at room temperature. The resulting mixturewas concentrated under vacuum. This resulted in 120 mg (80%) of thetitle compound as a yellow solid. LCMS (ESI, m/z): [M+H]⁺=296.9.

1-(5-Bromo-1-benzothiophen-2-yl)-4-[[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]piperazine (Compound 15c): To a solution of Compound 15b (150 mg, 0.50mmol) and3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole-4-carbaldehyde (143mg, 0.50 mmol) in dichloromethane (10 mL) was added acetic acid (30 mg,0.50 mmol). The reaction was stirred at r.t. for 30 min, then NaBH(OAc)₃(318 mg, 1.5 mmol) was added into the mixture. The resulting solutionwas stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 180mg (63%) of the title compound as a white solid. LCMS (ESI, m/z):[M+H]⁺=566.2.

2-(4-[[3-(2,6-Dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methyl]piperazin-1-yl)-1-benzofuran-5-carboxylicacid (Compound X-01): To a solution of Compound 15c (80 mg, 0.14 mmol)in tetrahydrofuran (1 mL) was added a solution of n-BuLi in hexane(0.056 mL, 0.14 mmol) at −78° C. The resulting solution was stirred for30 min at this temperature. CO₂ gas was bubbled into the mixture at −78°C. until saturated. The mixture was allowed warm to room temperature andstirred for another 1 h. The reaction was then quenched by the additionof 1 mL of water. The pH value of the mixture was adjusted to 3 with HCl(2 N). The resulting solution was extracted with 3x5 mL ofdichloromethane and the organic layers were combined. The resultedmixture was washed with water and brine. The residue was concentratedunder vacuum after dried over anhydrous sodium sulfate. The residue wasapplied onto a silica gel column with dichloromethane/methanol (20:1).This resulted in 40 mg (53%) of the title compound as a white solid.LCMS (ESI, m/z): [M+H]⁺=530.3. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 12.67(s, 1H), 8.05 (s, 1H), 7.80-7.74 (s, 1H), 7.66-7.50 (s, 4H), 6.37 (s,1H), 3.45-3.35 (s, 1H), 3.28 (s, 2H), 3.06-2.98 (m, 4H), 2.42-2.34 (m,4H), 1.34 (d, J=6.9 Hz, 6H).

Biological Assays

The compounds of the present technology may be assayed using thefollowing procedures and show or will be shown to have FXR bindingactivity.

FXR Transactivation Assay Reagents:

-   HEK293T-   pGL4.35[luc2P/9XGAL4 UAS/Hygro]-   pBIND-FXR Vector-   DMEM medium, high glucose-   Fetal Bovine Serum (FBS, heat-inactivated)-   Penicillin-Streptomycin (10000 U/m1,100 ml)-   DMEM, High Glucose, HEPES, no Phenol Red-   Opti-MEM® I Reduced Serum Medium-   Steady-Glo™ Luciferase Assay System-   TransIT-293 Transfection Reagent-   GW4064 as a positive control

Process:

-   1. Hek293T cells were plated at 1.1*10⁶/ml into a 100 mm dish.-   2. Cells were transfected with 8.4 μg of pBind-FXR, 1.26 μg of the    reporter vector pGL4.35 (Promega). Cells were incubated at 37° C.    under 5% CO2 atmosphere.-   3. All of compounds were 3-fold serial diluted from 10 mM stock for    10 doses in DMSO.-   4. Transfer compound dilutions into 384 well assay plates using    liquid workstation.-   5. Seed 25 ul HEK293T cells into 384 well assay plate (prepared    step 4) at 0.6*10⁵/ml. Cells were incubated at 37° C. under 5% CO2    atmosphere overnight.-   6. Add 25 ul steady-Glo™ Luciferase Assay Reagent into each well of    384-well assay plate.-   7. Record the luminescence value on Envision 2104 plate reader.-   8. Calculate EC50 by fitting % Activity values and log of compound    concentrations to nonlinear regression (dose response—variable    slope) with Graphpad 5.0.

FXR Coactivator Assay Reagents:

-   LanthaScreen™ TR-FRET Farnesoid X Receptor Coactivator Assay-   GW4064 as a positive control

Process:

-   1. All of compounds were 3-fold serial diluted from 10 mM stock for    10 doses in DMSO.-   2. Dilute each 100× agonist serial dilution to 2× using Complete    Coregulator buffer G.-   3. Transfer 10 μl of each of the 2× agonist serial dilutions to 384    well assay plates.-   4. Add 5 μl of 4× FXR-LBD to 384 well assay plates.-   5. Add 5 μl of 4× peptide/4× antibody solution to 384 well assay    plates.-   6. Incubate at room temperature protected from light.-   7. Read the plate at wavelengths of 520 nm and 495 nm on Envision    2104 plate reader.-   8. Calculate the TR-FRET ratio by dividing the emission signal at    520 nm by the emission signal at 495 nm.-   9. Calculate EC50 by fitting % Activity values and log of compound    concentrations to nonlinear regression (dose response—variable    slope) with Graphpad 5.0.

Results of the above assays with the present compounds are shown inTable 9.

TABLE 9 FXR Coactivator and Transactivation Assays FXR FXRTransactivation Coactivator Assay Assay Compound (EC₅₀) (EC₅₀) II-01 B AII-02 A A II-03 B A II-04 B A II-05 A A II-06 A — II-07 C — II-08 A AII-09 A A II-10 B — II-11 B A II-12 A — II-13 A A II-14 C — II-15 A —II-16 B A II-17 C — II-18 A A II-19 B A II-20 B A II-21 B — II-22 B AII-23 C — II-24 A A II-25 B — II-26 A A II-27 A — II-28 B A II-29 C —II-30 B A II-31 C — II-32 A A II-33 B A II-34 A — II-35 C — II-36 A —II-37 B — II-38 C — II-39 B — II-40 B A II-41 C — II-42 B A II-43 B AII-44 C — II-45 A — II-46 — A II-47 — B II-48 — B II-49 C — II-50 A —II-51 — A III-01 B — III-02 C — III-03 A — III-04 C — III-05 C — III-06C — III-07 A — III-08 C — III-09 C B III2-01 — A III3-01 — C IV-01 A AIV-02 A — IV-03 B — IV-04 A — IV-05 C — IV-06 B — IV-07 C — IV-08 A —IV-09 C — IV-10 B — V-01 B — V-02 A — VI-01 B A VI-02 A — VI-03 B —VI-04 A A VI-05 C — VI-06 B — VI-07 B — VI-08 C — VI-09 A — VI-10 C —VI-11 C — VII-01 A A VII-02 A — VII-03 A — VII-04 A — VII-05 — A VIII-01B A VIII-02 A A VIII-03 B — VIII-04 C — VIII-05 A — VIII-06 C — VIII-07B — IX-01 C — IX-02 C — X-01 C — A: EC₅₀ = 10 nM to 100 nM; B: EC₅₀ =101 nM-400 nM C: EC₅₀ = 401 nM-5 uM

Equivalents

While certain embodiments have been illustrated and described, a personwith ordinary skill in the art, after reading the foregoingspecification, can effect changes, substitutions of equivalents andother types of alterations to the compounds of the present technology orsalts, pharmaceutical compositions, derivatives, prodrugs, metabolites,tautomers or racemic mixtures thereof as set forth herein. Each aspectand embodiment described above can also have included or incorporatedtherewith such variations or aspects as disclosed in regard to any orall of the other aspects and embodiments.

The present technology is also not to be limited in terms of theparticular aspects described herein, which are intended as singleillustrations of individual aspects of the present technology. Manymodifications and variations of this present technology can be madewithout departing from its spirit and scope, as will be apparent tothose skilled in the art. Functionally equivalent methods within thescope of the present technology, in addition to those enumerated herein,will be apparent to those skilled in the art from the foregoingdescriptions. Such modifications and variations are intended to fallwithin the scope of the appended claims. It is to be understood thatthis present technology is not limited to particular methods, reagents,compounds, compositions, labeled compounds or biological systems, whichcan, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only,and is not intended to be limiting. Thus, it is intended that thespecification be considered as exemplary only with the breadth, scopeand spirit of the present technology indicated only by the appendedclaims, definitions therein and any equivalents thereof.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group. Each of the narrowerspecies and subgeneric groupings falling within the generic disclosurealso form part of the invention. This includes the generic descriptionof the invention with a proviso or negative limitation removing anysubject matter from the genus, regardless of whether or not the excisedmaterial is specifically recited herein.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

All publications, patent applications, issued patents, and otherdocuments (for example, journals, articles and/or textbooks) referred toin this specification are herein incorporated by reference as if eachindividual publication, patent application, issued patent, or otherdocument was specifically and individually indicated to be incorporatedby reference in its entirety. Definitions that are contained in textincorporated by reference are excluded to the extent that theycontradict definitions in this disclosure.

Other embodiments are set forth in the following claims, along with thefull scope of equivalents to which such claims are entitled.

What is claimed is:
 1. A compound according to formula I

stereoisomers, and/or salts thereof wherein L and M are independentlyselected from N and CR⁷, provided that at least one of L and M is N; Zis a substituted or unsubstituted C₁-C₄ alkylene group; W is

X is

D is N or CR⁹; G⁴ is CR¹³; G¹, G², G³ are selected from the groupconsisting of CH and CR¹¹; Q is O, S, or NR¹²; R¹ and R² areindependently H, OH, halo, CN, carboxyl, NR^(a)R^(b), or a substitutedor unsubstituted alkyl, alkoxy, or hydroxyalkyl group; R³ is asubstituted or unsubstituted alkyl or cycloalkyl group; R⁴ is CN, SO₃H,CONR^(a)R^(b), SO₂NR^(a)R^(b), NHSO₂R^(b), SO₂NHCOR^(a), CO₂R^(c), or asubstituted or unsubstituted tetrazolyl or1,2,4-oxadiazol-5(4H)-one-3-yl group; R⁷ is H, OH, halo, CN, carboxyl,amido, NR^(a)R^(b), or a substituted or unsubstituted alkyl, alkoxy,hydroxyalkyl, or aminoalkyl group; R⁹ is H, halo, or a substituted orunsubstituted C₁-C₆ alkyl, or O—(C₁-C₆ alkyl) group; R¹⁰ at eachoccurrence is independently halo, CO₂R^(c), or a substituted orunsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl, or fluorinatedcycloalkyl group, or, when n is 2 or 3, two of the R¹⁰ groups togethermay be a substituted or unsubstituted C2-C5 alkylene, heteroalkylene,alkenylene or heteroalkenylene group having 2 separate points ofattachment to the same carbon or different carbons of the nitrogencontaining ring to which it is attached; R¹¹ at each occurrence isindependently OH, halo, CF₃, CN, carboxyl, NR^(a)R^(b), or a substitutedor unsubstituted alkyl, alkoxy group, or phenyl group; R¹² is H or asubstituted or unsubstituted C₁-C₆ alkyl group; and R¹³ is halo, or asubstituted or unsubstituted C₁-C₆ alkyl, or O—(C₁-C₆ alkyl) group;R^(a) at each occurrence is independently H, or a substituted orunsubstituted alkyl, haloalkyl, cycloalkyl, aryl, or SO₂-alkyl group;R^(b) at each occurrence is H or a substituted or unsubstituted alkyl,or haloalkyl group; R^(c) is H or a substituted or unsubstituted alkyl,alkenyl, alkynyl, or cycloalkyl group; n is 0, 1, 2, 3, or 4; and r andt are each independently 1, 2, or
 3. 2. The compound of claim 1, whereinZ is an unsubstituted C₁-C₄ alkylene group.
 3. The compound of claim 2,wherein W is


4. The compound of claim 3, wherein X is

wherein q is 0, 1, or
 2. 5. The compound of claim 4 according to FormulaIA or Formula IB:

wherein r is 1 or 2; and t is
 2. 6. The compound of claim 5 according toFormula IA, wherein L is N.
 7. The compound of claim 6 wherein n is 2 or3 and two of the R¹⁰ groups together are a substituted or unsubstitutedC2-C5 alkylene, heteroalkylene, alkenylene or heteroalkenylene grouphaving 2 separate points of attachment to the same carbon or differentcarbons of the nitrogen containing ring to which it is attached.
 8. Thecompound of claim 7 wherein two of the R¹⁰ groups together are asubstituted or unsubstituted C2-C5 alkylene group having 2 separatepoints of attachment to the same carbon or different carbons of thenitrogen containing ring to which it is attached.
 9. The compound ofclaim 5 according to formula IA, wherein L is CR⁷.
 10. The compound ofclaim 9, wherein n is
 0. 11. The compound of claim 9, wherein n is 1 or2.
 12. The compound of claim 11 wherein R¹⁰ at each occurrence isindependently halo, CO₂R^(c), or a substituted or unsubstituted alkyl,alkoxy, hydroxyalkyl, cycloalkyl, or fluorinated cycloalkyl group. 13.The compound of claim 3 according to Formula IB, wherein M is CR⁷. 14.The compound of claim 13, wherein n is
 0. 15. The compound of claim 13,wherein n is 1 or
 2. 16. The compound of claim 15 wherein R¹⁰ at eachoccurrence is independently halo, CO₂R^(c), or a substituted orunsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl, or fluorinatedcycloalkyl group.
 17. The compound of claim 5, wherein R⁴ is CO₂H, CN,CONH₂, SO₂NH₂, or a substituted or unsubstituted CO₂—C₁-C₆ alkyl,CO₂—C₃-C₆ cycloalkyl, CONH—C₁-C₆ alkyl, CONH—C₃-C₆ cycloalkyl,NH—SO₂—C₁-C₆ alkyl, or tetrazolyl group.
 18. The compound of claim 17,wherein R⁴ is CO₂H, CONH₂, or a tetrazolyl group.
 19. The compound ofclaim 5, wherein R¹ and R² are independently halo, CN, CO₂R^(e),NR^(e)R^(f), or a substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ hydroxyalkyl group; and wherein R^(e) and R^(f) at eachoccurrence are independently H or a substituted or unsubstituted C₁-C₆alkyl group.
 20. The compound of claim 19, wherein R¹ and R² are bothCl.
 21. The compound of claim 5, wherein R³ is a substituted orunsubstituted C₁-C₆ alkyl or C₃-C₆ cycloalkyl group.
 22. The compound ofclaim 5, wherein R³ is an isopropyl or cyclopropyl group.
 23. Thecompound of claim 5, wherein X is


24. The compound of claim 23, wherein R¹¹ at each occurrence isindependently halo, CF₃, or a substituted or unsubstituted alkyl,alkoxy, or phenyl group.
 25. The compound of claim 23, wherein R¹³ is F,or a substituted or unsubstituted C₁-C₃ alkyl, or O—(C₁-C₃ alkyl) group.26. The compound of claim 25, wherein R¹³ is F, CH₃, or O—CH₃.
 27. Thecompound of claim 23, wherein q is
 0. 28. A compound selected from thegroup consisting of compounds II-17, II-30, II-36, II-37, II-38, II-39,II-43, II-44, II-45, I-46, II-47, II-48, II-49, I-50, II-51, III-08,IV-10, and VI-11.
 29. A composition comprising the compound of claim 1and a pharmaceutically acceptable carrier.
 30. A pharmaceuticalcomposition comprising an effective amount of the compound of claim 1for treating an FXR-mediated disorder or condition selected from thegroup consisting of liver disease, hyperlipidemia, hypercholesteremia,obesity, metabolic syndrome, cardiovascular disease, gastrointestinaldisease, atherosclerosis, and renal disease.
 31. The pharmaceuticalcomposition of claim 30 wherein the disorder or condition is a liverdisease selected from the group consisting of primary biliary cirrhosis(PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosingcholangitis (PSC), nonalcoholic fatty liver disease (NAFLD),nonalcoholic steatohepatitis (NASH), liver fibrosis, and livercirrhosis.
 32. A method of treatment comprising administering aneffective amount of a compound of of claim 1, or administering apharmaceutical composition comprising an effective amount of a compoundof claim 1, to a subject suffering from an FXR-mediated disorder orcondition selected from the group consisting of liver disease,hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome,cardiovascular disease, gastrointestinal disease, atherosclerosis, andrenal disease.
 33. The method of claim 32, wherein the disorder orcondition is a liver disease selected from the group consisting ofprimary biliary cirrhosis (PB C), cerebrotendinous xanthomatosis (CTX),primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease(NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and livercirrhosis.
 34. A method comprising modulating FXR by contacting FXR withan effective amount of a compound of claim 1.